Heterocyclic compounds process for their preparation and pharmaceutical compositions containing them and their use in medicine

ABSTRACT

We describe substituted benzenesulfoximine compounds having anti-inflammatory activity, processes for their preparation, pharmaceutical compositions containing them, and their use in the treatment of inflammatory diseases.

This application is the U.S. national phase of international applicationPCT/IN03/00133 filed on 1 Apr. 2003, which designated the US and claimspriority of IN Application No. 327/MUM/2002 filed 5 Apr. 2002. Theentire contents of these applications are incorporated herein byreference.

FIELD OF INVENTION

The present invention relates to novel compounds of general formula (I),their analogs, their derivatives, their tautomeric forms, theirpharmaceutically acceptable salts, pharmaceutical compositionscontaining them, where G represents substituted or unsubstituted, singleor fused groups selected from aryl group, heteroaryl or heterocyclicgroups. Preferably, G represents the groups A, B, C, D, E & F asdescribed below. The present invention also relates to a process ofpreparing compounds of general formula (I), their analogs, derivatives,their tautomeric forms, their pharmaceutically acceptable salts,pharmaceutical compositions containing them, and novel intermediatesinvolved in their synthesis.

The compounds of the present invention are useful in the treatment ofinflammatory diseases, preferably, wherein prostaglandins play apathophysiological role. Their role have been implicated in a number ofdiseases which includes rheumatoid arthritis and osteoarthritis,pyrexia, asthma, bone resorption, cardiovascular diseases, dysmenorrhea,premature labour, nephritis, nephrosis, atherosclerosis, hypotension,shock, pain, cancer, and alzheimer disease.

BACKGROUND OF THE INVENTION

Inflammation is a disorder, which is characterized by redness, fever,swelling and pain. Prostaglandins play a major role in the inflammationprocess and inhibition of prostaglandin production, especially of PGG₂,PGH₂ and PGE₂ has been a common target to treat inflammation. However,NSAIDs that are commonly used to treat prostaglandin-induced pain andinflammation also effect other prostaglandin-regulated processes notassociated with inflammation process. This leads to severe side effectsincluding life threatening gastric ulcers dyspepsia & nephrotoxicity,thereby reducing their therapeutic use.

Previously, NSAIDs have been found to prevent the production ofprostaglandins by inhibiting enzymes in the human arachidonicacid/prostaglandin pathway, including the enzyme cyclooxygenase (COX).In early 1990s, COX was demonstrated to exist as two distinct isoformsCOX-1 and COX-2 (PNAS (1991) 88, 2692-96) and recently a third isoformCOX-3 has been discovered from brain (PNAS (2002) 99, 13926-13931).COX-1 & COX-2 serve different physiological and pathophysiologicalfunctions. COX-1 is the constitutive isoform & is mainly responsible forthe synthesis of cytoprotective prostaglandins in the GI tract and forthe synthesis of thromboxane, which triggers platelet aggregation inblood platelets. COX-2 is believed to be an inducible isoform, which isstimulated in response to endotoxins, cytokines, and mitogens.Importantly, COX-2 plays a major role in prostaglandin biosynthesis ininflammatory cells (monocytes/macrophages) and in the central nervoussystem. (Current Medicinal Chemistry (2000) 7, 1041-62). The use ofCOX-2 as anti-cancer agents is discussed in Curr Drug Targets 2001March; 2 (1):79-106. Hence, the difference in the function of COX-1 &COX-2 provides a goal of separating the toxicity, particularly relatedto the gastrointestinal tract from efficacy of NSAIDs by developingdrugs that are selective COX-2 inhibitors as anti-inflammatory,analgesic, and/or antipyretic agents. It is believed that thesecompounds would have minimum or no GI & hematologic liabilities fromCOX-1 inhibition that plague almost all currently marketed NSAIDs, mostof which inhibit both COX-1 & COX-2, with specificity for COX-1inhibition greatly exceeding that for COX-2 inhibition. Celecoxib andRofecoxib were the first two selective COX-2 inhibitors approved forselected markets for the treatment of certain inflammatory conditions.

Although, the concept of selectively inhibiting COX-2 in order to havebetter efficacy & safety looks quite very attractive, recent clinicalstudies have raised doubts about the long term efficacy of selectiveCOX-2 inhibitors. Celecoxib was not found to be any better than otherNSAIDs in long-term clinical study (BMJ (2002) 324, 1287-88). On theother hand highly selective COX-2 inhibitors produce adversecardiovascular effects that are not seen in non-selective COX inhibitors(Science (2002) 296, 539-541; JAMA (2001) 268 954-959).

The references below disclose anti-inflammatory compounds that areselective COX-2 inhibitors. Increasing number of publications & patentsemerging steadily indicates continuing efforts to find a safe andeffective anti-inflammatory agent. Such novel compounds, their methodsfor preparation are described in EP1006114, EP1099695, EP418845,EP554829, EP0863134, EP0714895, EP0799523, GB2294879, U.S. Pat. No.5,474,995, U.S. Pat. No. 5,486,534, U.S. Pat. No. 5,510,368, U.S. Pat.No. 5,686,460, U.S. Pat. No. 5,691,374, U.S. Pat. No. 5,710,140, U.S.Pat. No. 5,723,485, U.S. Pat. No. 5,776,967, U.S. Pat. No. 5,981,576,U.S. Pat. No. 5,922,742, U.S. Pat. No. 6,083,969, U.S. Pat. No.6,071,954, U.S. Pat. No. 6,071,936, U.S. Pat. No. 6,133,292, U.S. Pat.No. 6,143,892, U.S. Pat. No. 6,274,590, WO9415932, WO9427980, WO9500501,WO9515315, WO9515316, WO9515317, WO9515318, WO9518799, WO9603387,WO9603392, WO9606840, WO9609304, WO9610012, WO9616934, WO9619469,WO9621667, WO9623786, WO9624585, WO9625405, WO9631509, WO9636623,WO9637467, WO9638418, WO9636617, WO9703667, WO9703953, WO9713755,WO9714691, WO9716435, WO9727181, WO9734882, WO9737984, WO9746524,WO97727181, WO9804527, WO9807425, WO9807714, WO9811080 WO9813483,WO9816227, WO9821195, WO9822442, WO9825896, WO9841511, WO9841516,WO9843966, WO9852940, WO9910331, WO9910332, WO9912930, WO9915503,WO9923087, WO9935130, WO0026216, WO0052008, WO0024719, WO0134577,WO0140216.

In addition to COX, the enzyme lipoxygenase (LOX) also plays animportant role in inflammation, 5-LOX products such as LTB4, LTC4 andLTD4 are involved in a variety of pathological processes (Pharmacol Rev(2003), 55 195-227). Therefore, inhibition of 5-LOX activity may producebeneficial effects in inflammation. Studies have indicated that dualinhibitors of COX and LOX may have better safety profile (Pharmacol Res(2001), 43 429-436) than non-selective NSAIDs. The compounds of thepresent invention are useful in treating inflammatory conditions causedby increased activities of COX and/or LOX enzymes.

Cytokines are known to be involved in inflammatory processes. Tumornecrosis factor α(TNF-α) is described as a key proinflammatory mediatorin autoimmune diseases. This 26 kDa enzyme is membrane associated untilprocessed into a smaller (17 kDa) soluble form by TNF-α convertingenzyme (TACE). The compounds of the present invention are also useful inthe treatment of inflammatory diseases such as arthritis by inhibitingTNF-α, or TACE or by inhibiting the production of Tumor necrosisfactor-α.

SUMMARY OF THE INVENTION

The present invention describes a group of novel compounds useful in thetreatment of inflammatory diseases, cytokine related, specially, TNF-αmediated diseases, cyclooxygenase related diseases, like inflammationand pain. The novel compounds are defined by the general formula (I)wherein G represents substituted or unsubstituted, single or fusedgroups selcted from aryl group, heteroaryl or heterocyclic groupscontaining one or more heteroatom selected from O, S. N, preferably, Grepresents the groups A, B, C, D, E & F as described below:

The compounds of the present invention are useful in the treatment ofthe human or animal body, in particular for the treatment of pain, feveror inflammation, to inhibit prostanoid-induced smooth muscle contractionor for the prevention of colorectal cancer. They are also useful for therelief of pain, fever and inflammation of a variety of conditionsincluding rheumatic fever and neuropathic pain, symptoms associated withinfluenza or other viral infections, common cold, low back and neckpain, dysmenorrhoea, headache, toothache, sprains and strains, myostis,neuralgia, synovitis, bursitis, tendinitis, injuries following surgicaland dental procedures, post-operative inflammation including ophthalmicsurgery such as cataract and refractive surgery, menstrual cramps,premature labor, These compounds may also be used in the treatment ofarthritis, such as rheumatoid arthritis, spondyloarthropathies, goutyarthritis, osteoarthritis, systemic lupus erythematosus and juvenilearthritis, skin inflammation disorders such as psoriasis, eczema,burning and dermatitis with better efficacy, potency and minimum toxiceffects.

The main objective of the present invention thus is to provide novelcompounds of general formula (I), their analogs, derivatives, theirtautomeric forms, their pharmaceutically acceptable salts, theirpharmaceutically acceptable solvates and pharmaceutical compositionscontaining them or their mixtures.

Another objective of the present invention is to provide a process forthe preparation of novel compounds of general formula (I), theiranalogs, derivatives, their tautomeric forms, their pharmaceuticallyacceptable salts, pharmaceutically acceptable solvates andpharmaceutical compositions containing them.

The present invention also aims at providing pharmaceutical compositionscontaining compounds of general formula (I), their analogs, derivatives,their tautomeric forms, their pharmaceutically acceptable salts,solvates, and their mixtures having pharmaceutically acceptablecarriers, solvents, diluents and other media normally employed in theirmanufacture.

The compounds of the present invention provides a method of treatment ofcyclooxygenase mediated diseases, by administering a therapeuticallyeffective & non-toxic amount of the compound of formula (I) or theirpharmaceutically acceptable compositions to the mammals.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds of the present invention are defined by the generalformula (I) wherein G represents substituted or unsubstituted, single orfused groups selcted from aryl group, heteroaryl or heterocyclic groupscontaining one or more heteroatom selected from O, S, N, preferably, Grepresents the groups A, B, C, D, E & F as described below:

where R₁ represents hydrogen, substituted or unsubstituted groupsselected from alkyl, aralkyl, acyl, alkylsulfonyl, arylsulfonyl groups;R₂ represents alkyl, aralkyl, alkoxy or —NHR where R represents hydrogenor lower alkyl groups which may be suitably substituted;

-   X₁, X₂, X₃, X₄ may be same or different and represent-   hydrogen, cyano, nitro, halo, carboxyl, formyl, hydrazino, azido,    amino, thio, hydroxy, or substituted or unsubstituted groups    selected from alkyl which may be linear or branched, alkenyl    cycloalkyl, alkoxy, cycloalkoxy, cycloalkoxyalkyl, haloalkoxy,    hydroxyalkyl, alkoxyalkyl, thioalkyl, carboxyalkyl, haloalkyl,    aminoalkyl, cyanoalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl    alkoxycarbonylalkyl, acyl, acyloxy, acyloxyalkyl, aralkyl, aryloxy,    aralkoxy, aryloxyalkyl, aralkoxyalkyl, aralkenyl, acylamino,    akylamino, dialkylamino, aralkylamino, alkoxyamino, hydroxylamino,    alkoxycarbonyl, aralkoxycarbonyl, groups; two adjacent groups may    form a methylenedioxy or a ethylenedioxy group; when G represents    heterocycle “D”, then at least one of the groups defined by X₁, X₂,    X₃, X₄ is not hydrogen;-   R₃ is selected from substituted or unsubstituted alkyl, substituted    or unsubstituted single or fused groups selected from aryl,    aralkenyl, heteroaryl or heterocyclic groups: R₄ and R₅ is selected    from hydrogen atom, halogen atom, carboxy, substituted or    unsubstituted groups selected from linear or branched alkyl,    haloalkyl polyhaloalkyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl,    phenyl groups; Y represents O or S; W represents O or S;-   Suitable substituents on R₃ and R₄ may be selected from cyano,    nitro, halo, carboxyl, hydrazino, azido, formyl, amino, thio,    hydroxy, ONO₂, alkyl-ONO₂ or substituted or unsubstituted groups    selected from alkyl which may be linear or branched, perhaloalkyl,    alkoxy, hydrazinoalkyl, alkylhydrazido, acyl, acyloxy, oxo,    carboxyalkyl, haloalkyl, aminoalkyl, haloalkoxy, hydroxyalkyl,    alkoxyalkyl, thioalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl,    alkylsulfoximinyl, aryl, aralkyl, aryloxy, aralkyl, aryloxyalkyl,    aralkoxyalkyl, aryloxycarbonyl, alkoxycarbonyl, aralkoxycarbonyl,    alkoxycarbonylalkyl, amidino, carboxamidoalkyl, acylamino,    cyanoamidino, cyanoalkyl, N-aminocarbonylalkyl, N-arylaminocarbonyl,    carboxyalkylaminocarboxy, N-alkylamino, N,N-dialkylamino,    N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino,    N-alkyl-N-arylamino, N-alkylaminoalkyl, N,N-dialkylaminoalkyl,    N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl,    N-alkyl-N-arylaminoalkyl, arylthio, aralkylthio,    N-alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl,    N,N-dialkylaminosulfonyl, N-alkyl-N-arylaminosulfonyl,    alkoxycarbonyl, aminocarbonyl, cycloalkyl, heterocyclic,    heterocyclicalkyl, heteroaryl, heteroaralkyl, heteroaralkoxy,    sulfamyl groups; two adjacent groups may form a methylenedioxy or a    ethylenedioxy group;-   Suitable substituents on X₁, X₂, X₃, X₄ may be selected from cyano,    nitro, halo, carboxyl, hydrazino, azido, formyl, amino, thio,    hydroxy or substituted or unsubstituted groups selected from alkyl    which may be linear or branched, alkoxy, alkoxycarbonyl, acyl,    acylamino, acyloxy, hydrazinoalkyl, alkylhydrazido, carboxyalkyl,    haloalkyl, aminoalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl,    thioalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, aryl, aralkyl,    aryloxy, aralkoxy, aryloxyalkyl, aralkoxyalkyl, alkoxycarbonyl,    amidino groups;-   Where the term “alkyl” is used anywhere in the specification, either    alone or within other terms such as “haloalkyl”, “hydroxyalkyl”,    “alkylthio”, “alkylsulfonyl” etc. it includes linear or branched    radicals having one to ten carbon atoms. More preferred alkyl    radicals are “lower alkyl” radicals having one to six carbon atoms.    Examples of such radicals include but not limited to methyl, ethyl,    n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,    pentyl, iso-amyl, hexyl, isohexyl, heptyl, octyl etc. The term    “alkenyl” includes linear or branched radicals having at least one    carbon-carbon double bond of two to ten carbon atoms or, preferably,    two to six carbon atoms. Examples of such radicals include ethenyl,    n-propenyl, butenyl, and the like. The term “halo” means halogens    such as fluorine, chlorine, bromine or iodine atoms. The term    “haloalkyl” includes radicals wherein any one or more of the alkyl    carbon atoms is substituted with halogen atoms as defined above.    Examples include monohaloalkyl, dihaloalkyl, polyhaloalkyl and    similar radicals. A monohaloalkyl radical, for example, may have    either an iodo, bromo, chloro or fluoro atom within the radical.    Dihalo and polyhaloalkyl radicals may have two or more of the same    halo atoms or a combination or different halo radicals. The alkyl    group in haloalkyl group is a lower alkyl group and is termed lower    haloalkyl group. “Lower haloalkyl” includes radicals having 1-6    carbon atoms. Examples of haloalkyl radicals include fluoromethyl,    difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,    trichloromethyl, trichloroethyl, pentafluoroethyl,    difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,    difluoropropyl, and the likes. The term “hydroxyalkyl” includes    linear or branched alkyl radicals having one to ten carbon atoms any    one of which may be substituted with one or more hydroxyl radicals.    More preferred hydroxyalkyl radicals are “lower hydroxyalkyl”    radicals having one to six carbon atoms and one or more hydroxyl    radicals. Examples of such radicals include hydroxymethyl,    hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, and    hydroxyhexyl.

The terms “alkoxy” and “alkoxyalkyl” includes linear or branchedoxy-containing radicals each having alkyl portions of one to about tencarbon atoms, such as methoxy radical. Preferred alkoxy radicals are“lower alkoxy” radicals having one to six carbon atoms. Examples of suchradicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy. Theterm “alkoxyalkyl” also includes alkyl radicals having two or morealkoxy radicals attached to the alkyl radical that is, to formmonoalkoxyalkyl and dialkoxyalkyl radicals. Preferred alkoxyalkylradicals are “lower alkoxyalkyl” radicals having one to six carbon atomsand one or two alkoxy radicals. Examples of such radicals includemethoxymethyl, methoxyethyl, ethoxyethyl, methoxybutyl, methoxypropyland the like. The “alkoxy” or “alkoxyalkyl” radicals may further containsubstitution consisting of one or more halo atoms, such as fluoro,chloro or bromo, to provide “haloalkoxy” or “haloalkoxyalkyl” radicals.Examples of such radicals include fluoromethoxy, chloromethoxy,trifluoromethoxy, trifluoroethoxy, fluoroethoxy and the like.

The term “aryl”, alone or in combination, includes carbocyclic aromaticsystem containing one, two or three rings wherein such rings may beattached together in a pendant manner or may be fused. The term “aryl”includes aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl,indane and biphenyl. The term “heterocyclic” includes saturated,partially saturated and unsaturated ring-shaped radicals, theheteroatoms selected from either nitrogen, sulfur and oxygen. Examplesof saturated heterocyclic radicals include saturated 3 to 7 memberedheterocyclic group containing one or more heteroatoms selected from N, Oand S. Examples of such groups include but are not limited toaziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl,piperazinyl, 2-oxopiperidinyl, 4-oxopiperidinyl, 2-oxopiperazinyl,3-oxopiperazinyl, morpholinyl, thiomorpholinyl, 2-oxomorpholinyl,azepinyl, diazepinyl, oxazepinyl, thiazepinyl, oxazolidinyl,thiazolidinyl and the like: examples of partially saturated heterocyclicradicals include dihydrothiophene, dihydropyran, dihydrofuran,dihydrothiazole and the like; the term “heteroaryl” includes unsaturatedheterocyclic radicals. Examples of unsaturated heterocyclic radicals,also termed “heteroaryl” radicals include unsaturated 5 to 6 memberedheteromonocyclic, fused polycyclic heteroaryl or fused polycyclicheterocycle groups containing one or more heteroatoms selected from O,N, S. Example of such groups include but not limited to pyrrolyl,pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, triazolyl, (e.g., 4H-1,2,4-triazolyl,1H-1,2,3-tetrazolyl etc.), indolyl, isoindolyl, dihydroindolyl,benzofuryl, 2,3-dihydrobenzofuryl, chromanyl, benzopyran, thiochromanyl,benzothiopyran, benzodioxolyl, benzodioxanyl pyridyl, thienyl,benzothienyl, oxazolyl, benzimidazolyl, quinolyl, isoquinolyl,indazolyl, benzotriazolyl, tetrazolopyridazinyl, pyranyl, 2-furyl,3-furyl, pthalazinyl, quinazolinyl, quinolinyl, isoquinolinyl,benzoxazolyl, benzoxadiazolyl, thiazolyl, thiadiazolyl, benzothiazolyl,benzothiadiazolyl, benzofuran, benzothiophene, and the like. Theaforesaid “heterocyclic or heteroaryl group” may have 1 to 4substituents such as lower alkyl, haloalkyl, dihaloalkyl, trihaloalkyl,hydroxy, oxo, amino and lower alkylamino, lower alkoxy, halo, lowerthioalkyl, acyl, acylamino groups. Preferred heterocyclic radicalsinclude five to ten membered fused or unfused radicals and morepreferable examples of heteroaryl radicals include benzofuryl,2,3-dihydrobenzofuryl, benzothienyl, indolyl, dihydroindolyl, chromanyl,benzopyran, thiochromanyl, benzothiopyran, benzodioxolyl, benzodioxanyl,pyridyl, thienyl, thiazolyl, oxazolyl, furyl, pyrazinyl, pthalazinyl,quinazolinyl, quinolinyl, isoquinolinyl, benzoxazolyl, benzothiazolyl,and the like.

The tem “hydrazino” used herein, either alone or in combination withother radicals, denotes —NHNH—, suitably substituted with otherradicals, such as alkyl hydrazino, where an alkyl group, as definedabove is attached to a hydrazino group.

The term “sulfonyl”, used alone or in combination with other terms suchas alkylsulfonyl, denotes respectively divalent radicals —SO₂—.“Alkylsulfonyl”, includes alkyl radicals attached to a sulfonyl radical,where alkyl is defined as above. More preferred alkylsulfonyl radicalsare lower alkylsulfonyl radicals having one to six carbon atoms.Examples of such lower alkylsulfonyl radicals include methylsulfonyl,ethylsulfonyl and propylsulfonyl. The term “arylsulfonyl” includes arylradicals as defined above, attached to a sulfonyl radical. Examples ofsuch radicals include phenylsulfonyl. The terms “sulfamyl,”“aminosulfonyl” and “sulfonamidyl,” whether alone or used with termssuch as “N-alkylaminosulfonyl” and “N-arylaminosulfonyl”,“N,N-dialkylaminosulfonyl”, “N-alkyl-N-arylaminosulfonyl”, denotes asulfonyl radical substituted with an amine radical, forming asulfonamide (—SO₂NH₂). The terms “N-arylaminosulfonyl” and“N,N-dialkylaminosulfonyl” denote sulfamyl radicals substituted,respectively with one alkyl radical, or two alkyl radicals. Morepreferred alkylaminosulfonyl radicals are “lower alkylaminosulfonyl”radicals having one to six carbon atoms. Examples of such loweralkylaminosulfonyl radicals include N-methylaminosulfonyl,N-ethylaminosulfonyl, N-methyl-N-ethylaminosulfonyl and the like. Theterms “N-arylaminosulfonyl” and “N-alkyl-N-arylaminosulfonyl” denotesulfamyl radicals substituted respectively with one aryl radical or onealkyl and one aryl radical. Preferred N-alkyl-N-arylaminosulfonylradicals are lower N-alkyl-N-arylsulfonyl radicals having alkyl radicalsof one to six carbon atoms. Examples of such lowerN-alkyl-N-arylsulfonyl radicals are N-ethyl-phenylaminosulfonyl and thelike.

The terms “carboxy” or “carboxyl”, whether used alone or with otherterms, such as “carboxyalkyl”, denotes —CO₂H. The terms “alkanoyl” or“acyl” include radicals derived from carboxylic acids and include butnot limited to substituted or unsubstituted groups selected from formyl,acetyl, propionyl (propanoyl), butanoyl (butyryl), isobutanoyl(isobutyryl), valeryl (pentanoyl), isovaleryl, pivaloyl, hexanoyl,benzoyl or the like. The term “carbonyl” used either alone or with otherterms, such as “alkylcarbonyl”, denotes —(C═O)—. The term“alkylcarbonyl” includes radicals having a carbonyl radical substitutedwith an alkyl radical such as acyl or alkanoyl described above. The term“alkylcarbonylalkyl” denotes an alkyl radical substituted with an“alkylcarbonyl” radical. The term “alkoxycarbonyl” means a radicalcontaining an alkoxy radical, as defined above, attached via an oxygenatom to a carbonyl radical. Preferably, “lower alkoxycarbonyl” includesalkoxy radicals having one to six carbon atoms. Examples of such “loweralkoxycarbonyl” ester radicals include substituted or unsubstitutedmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl andhexyloxycarbonyl. The term “alkoxycarbonylalkyl” includes radicalshaving “alkoxycarbonyl”, as defined above substituted to an alkylradical. Preferred alkoxycarbonylalkyl radicals are “loweralkoxycarbonylalkyl” having lower alkoxycarbonyl radicals as definedabove attached to one to six carbon atoms for examplemethoxycarbonylmethyl, tert-butoxycarbonylethyl, andmethoxycarbonylethyl. The term “aminocarbonyl” when used separately orwith other terms such as “aminocarbonylalkyl”, “N-alkylaminocarbonyl”,“N-arylaminocarbonyl”, “N,N-dialkylaminocarbonyl”,“N-alkyl-N-arylaminocarbonyl”, “N-alkyl-N-hydroxyaminocarbonyl” and“N-alkyl-N-hydroxyaminocarbonylalkyl”, substituted or unsubstituted. Theterms “N-alkylaminocarbonyl” and “N,N-dialkylaminocarbonyl” denoteaminocarbonyl radicals which have been substituted with one alkylradical and with two alkyl radicals, respectively. Preferred are “loweralkylaminocarbonyl” having lower alkyl radicals as described aboveattached to aminocarbonyl radical. The terms “N-arylaminocarbonyl” and“N-alkyl-N-arylaminocarbonyl” denote aminocarbonyl radicals substituted,respectively, with one aryl radical, or one alkyl and one aryl radical.The term “aminocarbonylalkyl” includes alkyl radicals substituted withaminocarbonyl radicals.

The term “amidino” denotes an —C(═NH)—NH₂ radical. The term“cyanoamidino” denotes an —C(═N—CN)—NH₂ radical. The term“heterocyclicalkyl” includes heterocyclic-substituted alkyl radicals.More preferred heterocyclicalkyl radicals are “lower heterocyclicalkyl”radicals having one to six carbon atoms and a heterocyclic radical.Examples include such radicals as pyrrolidinylmethyl, pyridylmethyl andthienylmethyl. The term “aralkyl” includes aryl-substituted alkylradicals. Preferable aralkyl radicals are “lower aralkyl” radicalshaving aryl radicals attached to alkyl radicals having one to six carbonatoms. Examples of such radicals include benzyl, diphenylmethyl,triphenylmethyl, phenylethyl, diphenylethyl and the like. The aryl insaid aralkyl may be additionally substituted with halo, alkyl, alkoxy,haloalkyl, haloalkoxy, hydroxy, amino, acylamino, alkoxycarbonyl,alkylthio and the like. The terms benzyl and phenylmethyl areinterchangeable. The term “cycloalkyl” includes radicals having three toten carbon atoms. More preferred cycloalkyl radicals are “lowercycloalkyl” radicals having three to seven carbon atoms. Examplesinclude radicals such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and the like. The term “cycloalkenyl” includesunsaturated cyclic radicals having three to ten carbon atoms, such ascyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and the like.The term “alkylthio” includes radicals containing a linear or branchedalkyl radical attached to a divalent sulfur atom. Example of alkylthioare methylthio (CH₃—S—), ethylthio, butylthio, and the like. The term“alkylsulfinyl” includes radicals containing a linear or branched alkylradical attached to a divalent-S(═O)-atom.

The term “aminoalkyl” includes alkyl radicals substituted with aminoradicals. Preferred aminoalkyl radicals are “lower aminoalkyl” havingone to six carbon atoms. Examples include aminomethyl, aminoethyl andaminobutyl. The term “alkylaminoalkyl” includes aminoalkyl radicalshaving the nitrogen atom substituted with at least one alkyl radical.Preferred alkylaminoalkyl radicals are “lower alkylaminoalkyl” havingone to six carbon atoms attached to a lower aminoalkyl radical asdescribed above. The terms “N-alkylamino” and “N,N-dialkylamino” denoteamino groups which have been substituted with one alkyl radical and withtwo alkyl radicals, respectively. Preferred alkylamino radicals are“lower alkylamino” radicals having one or two alkyl radicals of one tosix carbon atoms, attached to a nitrogen atom. Suitable “alkylamino” maybe N,N-dimethylamino, N,N-diethylamino or the like. The term “arylamino”denotes amino groups which have been substituted with one or two arylradicals, such as N-phenylamino. The “arylamino” radicals may be furthersubstituted on the aryl ring portion of the radical. The term“aralkylamino” denotes amino groups which have been substituted with oneor two aralkyl radicals, such as N-benzylamino. The “aralkylamino”radicals may be further substituted on the aryl ring portion of theradical. The terms “N-alkyl-N-arylamino” and “N-aralkyl-N-alkylamino”denote amino groups which have been substituted with one aralkyl and onealkyl radical, or one aryl and one alkyl radical; respectively, to anamino group. The terms “N-arylaminoalkyl” and “N-aralkylaminoalkyl”denote amino groups which have been substituted with one aryl radical orone aralkyl radical, respectively, and having the amino group attachedto an alkyl radical. Preferred arylaminoalkyl radicals are “lowerarylaminoalkyl” having the arylamino radical attached to one to sixcarbon atoms. Examples of such radicals include N-phenylaminomethyl andN-phenyl-N-methylaminomethyl. The terms “N-alkyl-N-arylaminoalkyl” and“N-aralkyl-N-alkylaminoalkyl” denotes N-alkyl-N-arylamino andN-alkyl-N-aralkylamino groups, respectively, and having the amino groupattached to alkyl radicals. The term “acyl”, whether used alone, or withanother term such as “acylamino” denotes a radical provided by theresidue after removal of hydroxyl from an organic acid. The term“acylamino” includes an amino radical substituted with an acyl group.Examples of an “acylamino” radical is acetylamino or acetamido(CH₃C(═O)—NH—) where the amine may be further substituted with alkyl,aryl, or aralkyl. The term “arylthio” includes aryl radicals of six toten carbon atoms, attached to a divalent sulfur atom. An example of“arylthio” is phenylthio. The term “aralkylthio” includes aralkylradicals as described above, attached to a divalent sulfur atom. Anexample of “aralkylthio” is benzylthio. The term “aryloxy” includes arylradicals, as defined above, attached to an oxygen atom. Examples of suchradicals include phenoxy. The term “aralkoxy” includes oxy-containingaralkyl radicals attached through an oxygen atom to other radicals.Preferred aralkoxy radicals are “lower aralkoxy” radicals having phenylradicals attached to lower alkoxy radical as described above. The term“haloaralkyl” includes aryl radicals as defined above “carboxyhaloalkyl”includes carboxyalkyl radicals as defined above having halo radicalsattached to the alkyl portion. The term “aralkenyl” includes arylradicals attached to alkenyl radicals having two to ene carbon atoms,such as phenylbutenyl, and phenylethenyl or styryl.

Suitable groups and substituents on the groups may be selected fromthose described anywhere in the specification.

Particularly useful compounds according to the present inventionincludes5-(4-Fluorophenyl)-1-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole5-(4-Chlorophenyl)-1-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole5-(4-Methylphenyl)-1-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole5-(4-Methoxyphenyl)-1-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole1-(4-methylsulfoximinylphenyl)-5-(4-n-propoxyphenyl)-3-trifluoromethyl-1H-pyrazole5-(4-Ethoxyphenyl)-1-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole5-(4-Hydroxyphenyl)-1-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole5-(3-Chloro-4-fluorophenyl)-1-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole5-(3,4-Difluorophenyl)-1-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole5-(4-Fluoro-3-methylphenyl)-1-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole5-(4-Methoxy-3-methylphenyl)-1-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole5-(3-Chloro-4-methoxyphenyl)-1-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole5-(3-Bromo-4-methoxyphenyl)-1-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole5-(3-Fluoro-4-methoxyphenyl)-1-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole5-(3-Methoxy-4-methylphenyl)-1-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole1-(2-Fluoro-4-methylsulfoximinylphenyl)-5-(4-Methoxyphenyl)-3-trifluoromethyl-1H-pyrazole1-(3Fluoro-4-methylsulfoximinylphenyl)-5-(4-Methoxyphenyl)-3-trifluoromethyl-1H-pyrazole1-(4-Methylsulfoximinylphenyl)-5-phenyl-3-trifluoromethyl 1H-pyrazole1-(4-Methylsulfoximinylphenyl)-5-(1-naphthyl)-3-trifluoromethyl-1H-pyrazole5-(4-Methoxyphenyl)-3-methyl-1-(4-methylsulfoximinylphenyl)-1H-pyrazole1-(4-Methylsulfoximinylphenyl)-5-(4-nitrophenyl)-3-trifluoromethyl-1H-pyrazole5-(3-Methoxyphenyl)-1-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole5-(3,5-Difluoro-4-Methoxyphenyl)-1-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole5-(3-Hydroxy-4-methoxyphenyl)-1-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole5-(4-Methoxyphenyl)-1-(4-methylsulfoximinylphenyl)-1H-pyrazole-3-carboxylicacid3-(Hydroxymethyl)-5-(4-Methoxyphenyl)-1-(4-methylsulfoximinylphenyl)-1H-pyrazole5-(4-Methoxyphenyl)-1-(4-methylsulfoximinylphenyl)-1H-pyrazol-3-ylmethylhydrogensulphate5-{4-(2-Hydroxy-ethoxy)phenyl}-1-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole1-(4-Methylsulfoximinylphenyl)-5-(4-pyridyl)-3-trifluoromethyl-1H-pyrazole1-(4-Methylsulfoximinylphenyl)-5-(3-pyridyl)-3-trifluoromethyl-1H-pyrazole1-(4-Methylsulfoximinylphenyl)-5-(2-pyridyl)-3-trifluoromethyl-1H-pyrazole5-(4-Isopropoxyphenyl)-1-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole1-(4-Methylsulfoximinylphenyl)-5-(2-thiophenyl)-3-trifluoromethyl-1H-pyrazole5-(4-Methylsulfoxyminylphenyl)-1-phenyl-3-trifluoromethyl-1H-pyrazole.1-(4-Methoxyphenyl)-5-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole5-Ethyl-4-(4-methylsulfoximinylphenyl)-3-phenyl-isoxazole5-Methoxymethyl-4-(4-methylsulfoximinylphenyl)-3-phenyl-isoxazole3-(4-Fluorophenyl)-5-methyl-4-(4-methylsulfoximinylphenyl)-isoxazole3-(4-Chlorophenyl)-5-methyl-4-(4-methylsulfoximinylphenyl)-isoxazole3-Ethyl-4-(4-methylsulfoximinylphenyl)-5-phenyl-isoxazole5-Chloro-4-(4-methylsulfoximinylphenyl)-3-phenyl-isoxazole5-methyl-4-(4-methylsulfoximinylphenyl)-3-phenyl-isoxazole3-(4-Methoxyphenyl)-5-methyl-4-(4-methylsulfoximinylphenyl)-isoxazole3-(3,4-Dichlorophenyl)-4-(3-fluoro-4-methylsulfoximinylphenyl)-5H-furan-2-one3-(4-Chlorophenyl)-4-(3-fluoro-4-methylsulfoximinylphenyl)-5H-furan-2-one3-Phenyl-4-(3-fluoro-4-methylsulfoximinylphenyl)-5H-furan-2-one3-(3,4-Difluorophenyl)-4-(3-fluoro-4-methylsulfoximinylphenyl)-5H-furan-2-one3-(3,4-Dimethoxyphenyl)-4-(3-fluoro-4-methylsulfoximinylphenyl)-5H-furan-2-one3-(4-methoxyphenyl)-4-(3-fluoro-4-methylsulfoximinylphenyl)-5H-furan-2-one3-(4-Methylphenyl)-4-(3-fluoro-4-methylsulfoximinylphenyl-5H-furan-2-one5-Chloro-3-(4-methylsulfoximinylphenyl)-6′-methyl-[2,3′]bipyridinyl5-Chloro-3-(4-methylsulfoximinylphenyl)-[2,3′]bipyridinyl3-(3-Fluorophenyl)-4-(4-methylsulfoximinylphenyl)-3H-thiazol-2-one3-(3,4-Dichlorophenyl)-4-(4-methylsulfoximinylphenyl)-3H-oxazol-2-one3-(3,4-Dichlorophenyl)-4-(4-methylsulfoximinylphenyl)-3H-thiazol-2-one3-(2-Fluorophenyl)-4-(4-methylsulfoximinylphenyl)-3H-oxazol-2-one3-(4-Bromophenyl)-4-(4-methylsulfoximinylphenyl)-3H-oxazol-2-one4-(4-Methylsulfoximinylphenyl)-3-phenyl-3H-oxazol-2-one3-(3,4-Dichlorophenyl)-4-[4-(N-chloroacetyl)methylsulfoximinylphenyl]-3H-oxazol-2-one3-(3,4-Dichlorophenyl)-4-[4-(N-acetyl)methylsulfoximinylphenyl]-3H-oxazol-2-one3-(3,4-Dichlorophenyl)-4-[4-(N-methylsulfonyl)methylsulfoximinyl-phenyl]-3H-oxazol-2-one3-(3,4-Dichlorophenyl)-4-[4-{N-(4-methylphenyl)sulfonyl}-methylsulfoximinyl-phenyl]-3H-oxazol-2-one

The present invention also provides methods for the preparation of novelcompounds described in the general formula (I), their tautomeric forms,their derivatives, their analogs, their pharmaceutically acceptablesalts and their pharmaceutically acceptable solvates, wherein allsymbols are as defined earlier. The process comprising:

Oxidizing a compound of formula (P) to get a compound of formula (Q)which is iminated with suitable reagents get compound of formula (I)which may further be converted to their pharmaceutically acceptablesalts, if desired.

A detailed process with different G groups are outlined in the schemes:Method B:

The mercapto compounds of formula P may be converted to the respectivesulfoxides of formula Q by reacting with an oxidizing agent. Suitableoxidizing agents may be selected from but not limited to peroxides andperoxyacids and their salts. Suitable oxidizing agent is selected fromH₂O₂, meta-peroxides of Na, K, and the like, oxone®, sodium perborate,sodium tungstate and the like, peracetic acid, m-chloroperbenzoic acid,magnesium monoperoxyphthalate, and the like. Suitable solvents are basedon the oxidizing agents used and are selected from water, acetic acid,acetonitrile, dichloromethane, acetone, THE, methanol, ethanol and thelike or a mixture thereof. Reaction temperature may range from −78° C.to 40° C., based on the solvent used.

Method C:

The sulfoxide compounds of formula Q may be converted to sulfoximinecompounds of formula (I) by reacting with suitable iminating agents suchas hydrazoic acid (HN₃) which may be generated by the reaction of NaN₃with conc. sulfuric acid in solvents such as CH₂Cl₂, CHCl₃ and the like.Temperature in the range −10° C. to reflux temperature of the solvent(s)used may be used. Alternatively, sulfoxides of formula IV or V may betreated with O-substituted hydroxylamines, such asO-mesitylenesulfonylhydroxylamine (MSH), followed by a base such as KOH,NaOH, NaHCO₃ and the like. Solvents such as CH₂Cl₂, CHCl₃ may be used.

-   -   i) Reacting a compound of formula II wherein, R₂, R₄, X₁, X₂,        X₃, X₄ are as defined earlier and Hal represents a halogen atom        such as chlorine, bromine or iodine atom with an aryl        thiocarbamate III to yield a compound of formula V, after        dehydration of the intermediate IV.    -   ii) Reacting the compound of formula V with an oxidizing        compound such as H₂O₂, peracids and such other oxidizing agents        to yield a sulfoxide of formula VI    -   iii) Reacting the sulfoxide of formula VI an appropriate        iminating agent such as HN₃ , O-substituted hydroxylamines such        as O-mesitylenesulfonyl hydroxylamine (MSH) and the like to        yield sulfoxamine of formula (IAa);    -   iv) optionally, compound of formula (IAa) is converted to        compound of formula (IA) by suitable agents to get appropriate        R₁ group. Alternatively, the compound of formula VI may be        converted to compound (IA) by treating with appropriate agents;    -   v) optionally, if desired, the compound of formula (IAa) or (IA)        are converted to pharmaceutically acceptable salts;

The reactions described in the processes (i) to (v) outlined above maybe performed by using the methods described herein:

Method A:

The haloketones of formula II may be converted to corresponding cycliccompounds of formula V by reacting with a compound of formula II,through an initial formation of a compound of formula IV, in a solventsuch as an alcohol like methanol, ethanol, isopropanol and the like;acetone, THF, dioxane, acetonitrile, toluene, xylene and the like or amixture thereof. Reaction temperature may range from ambient to refluxtemperature of the solvent(s) used. The compounds of formula IV isconverted to respective compound of formula V, by dehydration byrefluxing in a suitable medium such as an aqueous alcoholic mediumcontaining a mineral acid such as HCl or H₂SO₄, or H₃PO₄; organic acidssuch as PTSA may also be used in an organic solvent such as toluene,xylene and the like; organic acid such as acetic acid, propionic acid ortrifluoroacetic acid may also be used.

Method B:

The mercapto compounds of formula V may be converted to the respectivesulfoxides by reacting with an oxidizing agent. Suitable oxidizingagents may be selected from but not limited to peroxides and peroxyacidsand their salts. Suitable oxidizing agent is selected from H₂O₂,meta-peroxides of Na, K, and the like, oxone®, sodium perborate, sodiumtungstate and the like, peracetic acid, m-chloroperbenzoic acid,magnesium monoperoxyphthalate, and the like. Suitable solvents are basedon the oxidizing agents used and are selected from water, acetic acid,acetonitrile, dichloromethane, acetone, THF, methanol, ethanol and thelike or a mixture thereof. Reaction temperature may range from −78° C.to 40° C., based on the solvent used.

Method C:

The sulfoxide compounds of formula VI may be converted to sulfoximinecompounds by reacting with suitable iminating agents such as hydrazoicacid (HN₃) which may be generated by the reaction of NaN₃ with conc.sulfuric acid in solvents such as CH₂Cl₂, CHCl₃ and the like.Temperature in the range −10° C. to reflux temperature of the solvent(s)used may be used. Alternatively, sulfoxides of formula IV or V may betreated with O-substituted hydroxylamines, such asO-mesitylenesulfonylhydroxylamine (MSH), followed by a base such as KOH,NaOH, NaHCO₃ and the like. Solvents such as CH₂Cl₂, CHCl₃ may be used.

Method D:

The sulfoximines of formula (IAa) may be converted to correspondingsubstituted compounds of formula (IA) by reaction with appropriatealkylating/acylating agents in the presence of a base. Thealkylating/acylating agent depends on the desired group R₁ such assuitably substituted alkyl halides/acylhalides or acyl anhydrides. WhenR₁=Me, formic acid/formaldehyde mixture is used. Solvents used may beDMF, DMSO, acetone, THF, diaoxane, toluene, xylene and the like or amixture thereof. Bases such as K₂CO₃, Na₂CO₃, Na, KI, nBuLi Et₃N or amixture thereof may be used. Reaction temperature may range from 0° C.to reflux temperature of the solvent(s) used.

Method E:

The sulfoxide compounds of formula VI may be directly converted tosubstituted sulfoximine compounds by reacting with suitable reagentssuch as Tosylazide, Chloramine T, in solvents such as ethanol, methanoland the like, followed by basification to yield R₁=Tosyl groups.Alternatively, reaction with arylamines in the presence of t-BuOCl givesN-arylsulfoximines.

-   i) Reacting the compound of general formula VII with at least two    equivalents of an appropriate base followed by treatment with an    appropriate ester or anhydride to afford an alcohol of general    formula VIII;-   ii) heating the compound of general formula VIII in an appropriate    solvent in the presence of appropriate acid to get compound of    general formula IX.-   iii) Oxidizing compound of formula IX with appropriate oxidizing    agents to get a compound of general formula X;-   iv) Reacting sulfoxide of formula X with appropriate agents to    afford compound of general formula (IBb);-   v) Optionally compound of formula X may be converted to compound of    formula (IB) by suitable agents to get appropriate R¹ group.    Alternatively, compound of formula (IBb) may be converted to    compound of formula (IB) using appropriate agents.-   vi) Optionally, if desired, compounds of formula (IBb) or (IB) are    converted to pharmaceutically acceptable salts;

The reactions described in the processes outlined in the schemes IIabove may be performed by using the methods described herein:

Method F:

The oxime of formula VII may be converted to alcohol of formula VIII byreacting with two equivalents of a suitable base to produce a dianionwhich is further acylated. Bases such as n-BuLi, Sodium hydride, LDA,LiHMDS, NaHMDS and the like or a mixture thereof may be used.Temperature in the range of −78° C. to ambient temperature may be used.Preferably, the dianion formation is done at −78° to −40° C. range.Suitable acylating agents are esters, anhydrides, acyl imidazoles andthe like. The reaction is conducted under a blanket of inert atmosphereusing inert gases like N₂, He or Ar. Anhydrous condition is verycritical for the reaction to give good product and yield.

Method G:

The alcohol of formula VIII may be converted to isooxazole of formula IXby dehydration in the presence of an acid. Solvents such as ethanol,THF, toluene, xylene, and the like or a mixture thereof may be used.Suitable acids may, be PTSA, H₂SO₄, HCl, HBr, camphorsulfonic acid,pyridinium paratoluene sulfonic acid and the like. The amount acid usedmay be catalytic or substoichiometric or Stoichiometric to effect thedehydration. Temperature in the range of ambient to reflux temperatureof the solvent(s) may be used.

Method B:

The mercapto compound of formula IX may be converted to sulfoxide offormula X by reacting with an oxidizing agent as described in Method Bof scheme I earlier.

Method C:

The sulfoxide compounds of formula X may be converted to sulfoximinecompounds of formula (IBb) by reacting with suitable iminating agents asdescribed earlier in Method C of scheme I.

Method D:

The sulfoximines of formula (IBb) may be converted to compounds offormula (IB) by reaction with appropriate alkylating/acylating agents inthe presence of a base as described earlier in method D of scheme I.

Method E:

The compounds X may be directly converted to compounds of formula (IB)by reacting with suitable reagents as described earlier in Method E ofscheme I, such as Tosyl azide, Chloramine T, in solvents such asethanol, methanol and the like, followed by basification to yieldR₁=Tosyl groups. Alternatively, reaction with aryl amines in thepresence of t-BuOCl gives N-aryl sulfoximines as described in method Eof scheme I.

-   i. Reacting hydrazine of general formula XI with 1,3-diketone of    general formula XII to get compound of general formula XIII;-   ii. Oxidizing compound of formula XIII with appropriate oxidizing    agents to get a compound of general formula XIV;-   iii. Reacting sulfoxide of formula XIV with appropriate agents to    afford compound to of general formula (ICc);-   iv. Optionally compound of formula XIV may be converted to compound    of formula (IC) by suitable agents to get appropriate R¹ group.    Alternatively, compound of formula (ICc) may be converted to    compound of formula (IC) using appropriate agents.-   v. Optionally, if desired, compounds of formula (ICc) or (IC) are    converted to pharmaceutically acceptable salts;

The reactions described in the processes outlined in the scheme IIIabove may be performed by using the methods described herein:

Method H:

The hydrazene of formula XI or its acid addition salts may be convertedto compound of formula III by reacting with appropriately substituted1,3-diketones of formula XII. Reagents like sodium acetate may be usedbut not critical. Solvents such as alcohols like, ethanol, methanol,isopropanol and the like, THF, dioxane, toluene, xylene, cyclohexane,heptane, hexane, and the like or mixture thereof may be used.Temperature in the range 20° C. to reflux temperature of the solvent maybe used, preferably in the range 60° C. to reflux temperature of thesolvent(s) may be used. Inert atmosphere may be maintained using N₂, He,or argon gas.

Method B:

The pyrazole compound of formula XII may be converted to sulfoxide offormula XIV by reacting with an oxidizing agent as described earlier inmethod B of scheme I.

Method C:

The sulfoxide compounds of formula XIV may be converted to sulfoximinecompounds of formula (ICc) by reacting with suitable iminating agents asdescribed earlier in method C of scheme I.

Method D:

The sulfoximines of (ICc), may be converted to compounds of formula(IC), by reaction with appropriate alkylating/acylating agents in thepresence of a base as described earlier in method D of scheme I.

Method E:

The compounds XIV may be directly converted to compounds of formula(IC), by reacting with suitable reagents; such as Tosyl azide,Chloramine T, in solvents such as ethanol, methanol and the like,followed by basification to yield R₁=Tosyl groups. Alternatively,reaction with aryl amines in the presence of t-BuOCl gives N-arylsulfoximines as described in method E of scheme I.

The compound of XV in scheme IV above, may be converted to compound ofto general formula (ID) defined earlier, by a method which comprises:

-   i. Oxidizing compound of XV with appropriate oxidizing agents to get    a compound of general formula XVI;-   ii. Reacting sulfoxide of formula XVI with appropriate agents to    afford compound of general formula (IDd).-   iii. Optionally compound of formula (IDd) obtained in ii) above may    be converted to compound of formula (ID) by suitable agents to get    appropriate R¹ group.-   iv. Optionally, compound of formula XVI may be directly converted to    compound of formula (ID) using appropriate reagents.-   v. Optionally, if desired, compound of formula (IDd) or (ID) may be    converted to pharmaceutically acceptable salts;

The compound of general formula (ID) may be prepared by a processoutlined in scheme IV which comprises:

Method B:

The lactone compound of formula XV may be converted to sulfoxide offormula XVI by reacting with an oxidizing agent as described earlier inmethod B of scheme I.

Method C:

The sulfoxide compounds of formula XVI may be converted to sulfoximinecompounds of formula (IDd) by reacting with suitable iminating agents asdescribed earlier in method C of scheme I.

Method D:

The sulfoximines of (IDd) may be converted to compounds of formula (ID),by reaction with appropriate alkylating/acylating agents in the presenceof a base as described earlier in method D of scheme I.

Method E:

The compounds XVI may be directly converted to compounds of formula (ID)by reacting with suitable reagents; such as Tosyl azide, Chloramine T,in solvents such as ethanol, methanol and the like, followed bybasification to yield R₁=Tosyl groups. Alternatively, reaction with arylamines in the presence of t-BuOCl gives N-aryl sulfoximines as describedin method E of scheme I.

-   i. Reacting compound of formula XVII, with a compound of formula    XVIII to get the compound of formula XIX;-   ii. Oxidizing compound of XIX with appropriate oxidizing agents to    get a compound of general formula XX;-   iii. Reacting sulfoxide of formula XX with appropriate agents to    afford compound of (general formula (IEe);-   iv. Optionally compound of formula (IEe) obtained in iii) above may    be converted to compound of formula (IE) by suitable agents to get    appropriate R¹ group.-   v. Optionally, compound of formula XX may be directly converted to    compound of formula (IE) using appropriate reagents.-   vi. Optionally, if desired, compound of formula (Ee) or (E) may be    converted to pharmaceutically acceptable salts;

The compound of general formula (IE) may be prepared by a processoutlined in scheme V which comprises:

Method I:

The keto compound of the formula XVII, may be converted to compound offormula XIX by reacting with compound of formula XVIII Reagents likeammonium acetate may be used. Reaction may be carried out using solventslike propionic acid or without using solvent. Reaction temperatures mayrange between ambient and 150° C. or reflux temperature of thesolvent(s) used.

Method B:

The pyridine compound of formula XIX may be converted to sulfoxide offormula XX by reacting with an oxidizing agent as described earlier inmethod B of scheme I.

Method C:

The sulfoxide compounds of formula XX may be converted to sulfoximinecompounds of formula (IEe) by reacting with suitable iminating agents asdescribed earlier in method C of scheme I.

Method D:

The sulfoximines of (IEe), may be converted to compounds of formula(IE), by reaction with appropriate alkylating/acylating agents in thepresence of a base as described earlier in method D of scheme I.

Method E:

The compounds XX may be directly converted to compounds of formula (IE)by reacting with suitable reagents; such as Tosyl azide, Chloramine T,in solvents such as ethanol, methanol and the like, followed bybasification to yield R₁=Tosyl groups. Alternatively, reaction with arylamines in the presence of t-BuOCl gives N-aryl sulfoximines as describedin method E of scheme I.

-   i. Reacting hydrazine of general formula XXII with 1,3-diketone of    general formula XXI to get compound of general formula XXIII;-   ii. Oxidizing compound of formula XXIII with appropriate oxidizing    agents to get a compound of general formula XXIV;-   iii. Reacting sulfoxide of formula XXIV with appropriate agents to    afford compound of general formula (IFf);-   iv. Optionally compound of formula XXIV may be converted to compound    of formula (IF) by suitable agents to get appropriate R¹ group.    Alternatively, compound of formula (IFf) may be converted to    compound of formula (IF) using appropriate agents.-   v. Optionally, if desired, compounds of formula (IFf) or (IF) are    converted to pharmaceutically acceptable salts;

The reactions described in the processes outlined in the scheme VI abovemay be performed by using the methods described herein:

Method H:

The hydrazene of formula XXII or its acid addition salts may beconverted to compound of formula XXIII by reacting with appropriatelysubstituted 1,3-diketones of formula XXI. Reagents like sodium acetatemay be used but not critical. Solvents such as alcohols like, ethanol,methanol, isopropanol and the like, THF, dioxane, toluene, xylene,cyclohexane, heptane, hexane, and the like or mixture thereof may beused. Temperature in the range 20° C. to reflux temperature of thesolvent may be used, preferably in the range 60° C. to refluxtemperature of the solvent(s) may be used. Inert atmosphere may bemaintained using N₂, He, or argon gas.

Method B:

The pyrazole compound of formula XXIII may be converted to sulfoxide offormula XXIV by reacting with an oxidizing agent as described earlier inmethod B of scheme I.

Method C:

The sulfoxide compounds of formula XXIV may be converted to sulfoximinecompounds of formula (IFf) by reacting with suitable iminating agents asdescribed earlier in method C of scheme I.

Method D:

The sulfoximines of (IFf), may be converted to compounds of formula(IF), by reaction with appropriate alkylating/acylating agents in thepresence of a base as described earlier in method D of scheme I.

Method E:

The compounds XXIV may be directly converted to compounds of formula(IF) by reacting with suitable reagents; such as Tosyl azide, ChloramineT, in solvents such as ethanol, methanol and the like, followed bybasification to yield R₁=Tosyl groups. Alternatively, reaction with arylamines in the presence of t-BuOCl gives N-aryl sulfoximines as describedin method E of scheme I.

Pharmaceutically acceptable salts forming part of this invention areintended to define but not limited to salts of the carboxylic acidmoiety when present in the molecule such as alkali metal salts like Li,Na, and K salts; alkaline earth metal salts like Ca and Mg salts; saltsof organic bases such as lysine, arginine, guanidine and itsderivatives, which may be optionally substituted, diethanolamine,choline, tromethanine and the like; ammonium or substituted ammoniumsalts and aluminium salts. Salts may be acid addition salts whichdefines but not limited to sulfates, bisulfates, nitrates, phosphates,perchlorates, borates, hydrohalides, acetates, tartrates, maleates,fumarates, maleates, citrates, succinates, palmoates, methanesulfonates,benzoates, salicylates, hydroxynaphthoates, benzenesulfonates,ascorbates, glycerophosphates, ketoglutarates and the like.Pharmaceutically acceptable solvates may be hydrates or comprising othersolvents of crystallization such as alcohols.

It will be appreciated that in any of the above mentioned reactions anyreactive group in the substrate molecule may be protected, according toconventional chemical practice. Suitable protecting groups in any of theabove mentioned reactions are those used conventionally in the art. Themethods of formation and removal in such protecting groups are thoseconventional methods appropriate to the molecule being protected. T. W.Greene and P. G. M. Wuts “Protective groups in Organic Synthesis”, JohnWiley & Sons, Inc, 1999, 3^(rd) Ed., 201-245 along with referencestherein.

Acid addition salts, wherever applicable may be prepared by treatmentwith acids such as tartaric acid, mandelic acid, fumaric acid, malicacid, lactic acid, maleic acid, salicylic acid, citric acid, ascorbicacid, benzene sulfonic acid, p-toluene sulfonic acid, hydroxynaphthoicacid, methane sulfonic acid, acetic acid, benzoic acid, succinic acid,palmitic acid, hydrochloric acid, hydrobromic acid, sulfuric acid,nitric acid and the like in solvents such as water, alcohols, ethers,ethyl acetate, dioxane, THF, acetonitrile, DMF or a lower alkyl ketonesuch as acetone, or mixtures thereof.

Another aspect of the present invention comprises a pharmaceuticalcomposition, containing at least one of the compounds of the generalformula (I), their derivatives, their analogs, their tautomeric forms,their pharmaceutically acceptable salts, their pharmaceuticallyacceptable solvates thereof as an active ingredient, together withpharmaceutically employed carriers diluents and the like.

Pharmaceutical compositions containing a compound of the presentinvention may be prepared by conventional techniques, e.g. as describedin Remington: the Science and Practice of Pharmacy, 19^(th) Ed., 1995.The compositions may be in the conventional forms, such as capsules,tablets, powders, solutions, suspensions, syrups, aerosols or topicalapplications. They may contain suitable solid or liquid carriers or insuitable sterile media to form injectable solutions or suspensions. Thecompositions may contain 0.5 to 20%, preferably 0.5 to 10% by weight ofthe active compound, the remaining being pharmaceutically acceptablecarriers, excipients, diluents, solvents and the like. Due to theirmixed COX-1/COX-2 activity, the compounds of formula (I) represent goodanti-inflammatory compounds having less harmful side effects than theNSAIDs as well as selective COX-2 inhibitors.

The present invention provides a compound of formula (I) for use in amethod of treatment of the human or animal body by therapy, inparticular for the treatment of pain fever or inflammation, to inhibitprostanoid-induced smooth muscle contraction or for the prevention ofcolorectal cancer.

Another objective of the present invention is to provide for the use ofcompound of formula (I) in the manufacture of a medicament for thetreatment of pain, fever or inflammation, to inhibit prostanoid-inducedsmooth muscle contraction or for the prevention of colorectal cancer.

The compounds of the present invention are useful in the treatment ofinflammation and inflammation related disorders by administering thesubject a therapeutic amount of the compound of formula-I or its activesalt. Inflammation is associated with a variety of disease conditions. Alist of such disease conditions which can be treated by cyclooxygenaseinhibitors and COX-2 inhibitors in particular, are disclosed in U.S.Pat. Nos. 5,604,253 and 5,908,852 and WO 9638442, 9603392 and WO9714691. Such conditions includes pail, fever and inflammation of avariety of conditions including rheumatic fever, symptoms associatedwith influenza or other viral infections, common cold, low back and neckpain, dysmenorrhea, headache, toothache, sprains and strains, menstrualcramps, premature labor, Such compounds may also be used in thetreatment of arthritis, including but not limited to rheumatoidarthritis, spondyloarthropathies, gouty arthritis, osteoarthritis,systemic lupus erythematosus and juvenile arthritis. They may also beused in the treatment of skin inflammation disorders such as psoriasis,eczema, burning and dermatitis.

The compounds of formula (I) can also be used as alternative toconventional NSAIDs, particularly where such non-steroidalanti-inflammatory drugs may be contraindicated such as the treatment ofpatients with gastrointestinal disorders including peptide ulcers,gastritis, regional enteritis, ulcerative colitis, diverticulitis,Crohn's disease, inflammatory bowel syndrome and irritable bowlsyndrome, ulcerative colitis, Crohn's disease, gastrointestinal bleedingand coagulation disorders, kidney disease (e.g. impaired renalfunction), those prior to surgery or taking anticoagulants, and thosesusceptible to NSAIDs.

In addition, compounds of the present invention may inhibit cellularneoplastic transformations and metastatic tumour growth and hence usefulin the treatment of cancer. In particular, the present inventionprovides for a method for treating neoplasia that produces prostaglandinby treating the subject to a therapeutic amount of the compound (I).Thus the compounds of the present invention would be useful for theprevention and treatment of cancer, such as colorectal cancer and cancerof the lip, mouth, esophagus, breast, lung, prostate, bladder, pancreas,cervix and skin, small bowel cancer, stomach cancer ovary cancer,cervical cancer and the like. Use of COX-2 inhibitors in aforesaiddiseases are discussed in U.S. Pat. No. 5,972,986 and WO 0076983 &9714691. Such compounds will also be useful in the treatment ofinflammation in such diseases as vascular diseases, migraine headaches,periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease,sclerodoma, rheumatic fever, type I diabetes, neuromuscular junctiondisease including myasthenia gravis, white matter disease includingmultiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome,polymyositis, gingivitis, nephritis, hypersensitivity, swelling afterinjury, myocardial ischemia and the like. The compounds would also beuseful in the treatment of ophthalmic diseases such as retinitis,retinopathies, uveitis, ocular photophobia, and of acute injury to theeye tissue. They are also useful in the treatment of pulmonaryinflammation, such as that associated with viral infections and cysticfibrosis.

The compounds of the present invention would also be useful for thetreatment of certain central nervous system disorders, such as corticaldementias including Alzheimer's disease (Bratisl Lek Listy 2001; 102(3): 123-132) and central nervous system damage resulting from stroke,ischemia and trauma. These compounds will also be use in alleviatingneuropathic pain. The compounds of the invention are useful asanti-inflammatory agents, such as for the treatment of arthritis, withthe additional benefit of having significantly less harmful sideeffects. These compounds would be useful in the treatment of allergicrhinitis, respiratory distress syndrome, endotoxin shock syndrome andatherosclerosis.

The compounds of the present invention may also be useful in thetreatment of angiogenesis-mediated disorders. Angiogenesis mediateddisorders may be treated with cyclooxygenase inhibitors are described inU.S. Pat. No. 6,025,353 and WO 0076983. According to these patents suchdisorders include, for example, metastasis, corneal graft rejection,ocular neovascularization, diabetic retinopathty, retrolentalfibroplasia, neovascular glaucoma, gastric ulcer, infantilehemaginomas,angiofibroma of the nasopharynx, avascular necrosis of the bone andendometrosis.

Besides being useful for human treatment, these compounds are alsouseful for veterinary treatment of companion animals, exotic animals andfarm animals including mammals, rodents, and the like. More preferredanimals include horses, dogs and cats.

The present compounds may also be used as co-therapies, partially orcompletely, in place of other conventional anti-inflammants likesteroids, NSAIDs, 5-lipoxygenase inhibitors, LTB₄ receptor antagonistsand LTA₄ hydrolase inhibitors. They can also be used in combinationtherapies with opoids and other analgesics, including narcoticanalgesics, Mu receptor antagonists, Kappa receptor antagonists,non-narcotic analgesics, monoamine uptake inhibitors, adenosineregulating agents, cannabinoid derivatives, substance P antagonists,neurokinin-1 receptor antagonists and sodium channel blockers amongothers.

The present invention also relates to a pharmaceutical composition forthe treatment of a disorder or condition that can be treated byinhibition COX in a mammal, preferably a human, cat, livestock or dog,comprising a COX inhibiting effective amount of a compound of formula(I) or a pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.

The present invention also relates to a method for treating a disorderor condition that can be treated or prevented by inhibiting COX in amammal, preferably a human, cat, dog livestock, comprising administeringto a mammal requiring such treatment a COX inhibiting effective amountof a compound of formula (I) or a pharmaceutically acceptable saltthereof.

This invention also relates to a method of or a pharmaceuticalcomposition for the treatment of inflammation and similar diseases whichcomprises administering a compound of formula (I) of this invention orits salt to a mammal including a human, cat, livestock or dog. The saidinhibitory compound is used in combination with one or more othertherapeutically active agents such as:

-   A) In a condition where a joint has become inflamed along with a    bacterial, fungal, protozoal, and/or oral infection, said inhibitory    compound is administered in combination with one or more antibiotic,    antifungal, antiprotozoal, and/or antiviral therapeutic agents.    -   i) During multi-fold treatment of pain and inflammation is        required, the compound should be administered in combination        with inhibitors of other mediators of inflammation, consisting,        of members of the following groups: NSAIDS, H₁-receptor        antagonists, kinin-B₁- and B₂-receptor antagonists;        prostaglandin inhibitors selected from the group consisting of        PGD-, PGF-, PGI₂-, and PGE-receptor antagonists; thromboxane A₂        (TXA₂-) inhibitors; 5-, 12- and 15-lipoxygenase inhibitors;        leukotriene LTC₄-, LTD₄/LTE₄-, and LTB₄-inhbitors; PAF-receptor        antagonists; anti-inflammatory glucocorticoids; anti-gout agents        including colchicine; xanthine oxidase inhibitors including        allopurinol; and uricosuric agents selected from probenecid,        sulfinpyrazone, and benzbromarone.-   B) When treating older mammals with geriatric disorders, the said    compound is administered in combination with members selected from    any of the following groups: cognitive therapeutics,    anti-hypertensives and other cardiovascular drugs selected from    among diuretics, vasodilators, β-adrenergic receptor antagonists,    ACE inhibitors alone or in combination with neutral endopeptidase    inhibitors intending to offset the consequences of atherosclerosis,    hypertension, myocardial ischemia, angina, congestive heart failure,    and myocardial infarction

For the treatment of any of the above-mentioned diseases the compoundsof formula (I) may be administered, for example, orally, topically,parenterally, by inhalation spray or rectally in dosage unitformulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles.

The compounds of the present invention is useful in the treatment ofinflammatory diseases caused by cytokines, specially, TNF-α, by eitherinhibiting the production or by inhibiting the TNF-α converting enzyme(TACE) or by inhibiting TNF-α itself.

In general, the dosage for humans will range preferentially from 0.01 mgto 100 mg per kg of body weight per day, although variations will occur,depending upon the weight, sex and condition of the subject beingtreated, the state of the disease being treated and the particular routeof administration. However, the preferred dosage level should be in therange of from 0.1 mg to 10 ma per kg of body weight per day in single ordivided dosage.

For non-human mammals e.g. dogs, cats, horses or other livestock thedosage should be from about 0.01 mg/g to about 20.0 mg/kg/day, and morepreferably from about 0.5 mg/kg to about 8.0 mg/kg/day.

The compounds of the present invention may be administered alone or incombination with pharmaceutically acceptable carriers or diluents by anyof the routes as previously indicated, in single or multiple doses. Morespecifically, the novel compounds described in the invention can beadministered in a wide variety of different dosage forms, i.e., they maybe combined with various pharmaceutically acceptable inert carriers inthe form of tablets, capsules, lozenges, trochees, hard candies,powders, sprays, creams, salves, suppositories, jellies, eels, pastes,lotions, ointments, aqueous suspensions, injectable solutions, elixirs,syrups, and the like. The carriers may include solid diluents orfillers, sterile aqueous media and various nontoxic organic solventsetc. Moreover, for oral consumption, the pharmaceutical compositions canbe suitably sweetened and/or flavored. In general, thetherapeutically-effective compounds as described in the invention arepresent in the compositions at concentration levels ranging from 5% to60% by weight, preferably 10% to 50% by weight.

For oral administration, the tablets may be combined with variousexcipients such as microcrystalline cellulose, sodium citrate, calciumcarbonate, dipotassium phosphate and glycine along with variousdisintegrants such as starch more preferably corn, potato or tapiocastarch, alginic acid, sodium carbonate and certain complex sillicates;together with binders like polyvinylpyrrolidone, sucrose, gelatin andacacia, humectants such as for example, glycerol; solution retardingagents, such as, for example paraffin; absorption accelerators such as,for example, quartenary ammonium compounds; wetting agents like cetylalcohol and glycerol monostearate; absorbents like kaolin and bentoniteclay. Additionally, magnesium stearate, sodium lauryl sulfate, talc,calcium stearate, solid polyethylene glycols and mixtures thereof areoften added as lubricating agents for tabletting purposes. In the caseof capsules, tablets and pills, the dosage form may also comprisebuffering agents.

Similar type of solid compositions may also be employed as fillers andexcipients in soft and hard gelatine capsules; preferred materialsinclude lactose, milk sugar or high molecular weight polyethyleneglycols.

The active compounds can also be in micro-encapsulated form using one ormore of the excipients noted above. The solid dosage forms of tablets,dragees, capsules, pills, and the granules can be prepared with coatingsand shells such as enteric coatings, release controlling coatings andother coatings which are well known in the field of pharmaceuticalformulation art. In such solid dosage forms the active compound may beadmixed with at least one inert diluent such as sucrose, lactose andstarch. They may also contain, additional substances for e.g. tabletinglubricants and other substances like magnesium stearate andmicrocrystalline cellulose. In the case of capsules, tablets, and pills,the formulation may also contain buffering agents. They may also be soformulated that they release the active ingredient(s) only orpreferentially in a certain part of the intestinal tract, optionally ina delayed manner. The same may be achieved using embedded agents like,for example, polymeric substances and waxes.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups,and elixirs. For such oral consumption it is desirable to combine theactive ingredient with various sweetening or flavoring agents, coloringmatter or dyes, if so desired. The diluents may be selected from water,ethanol, propylene glycol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, 1,3 butylene glycol, dimethylformamide, oils for e.g. cottonseed, groundnut, corn, germ, olive,castor, sesame oils and the like, glycerol, tetrahydrofurfuryl alcohol,polyethylene glycols and esters of fatty acids like sorbitan and variouscombination thereof. For mammals other than humans, the composition ofthe active substance are suitably modified.

For parenteral administration, the solutions of the compound is preparedin either sesame or peanut oil or in aqueous propylene glycol. Theaqueous solutions should be suitably buffered if necessary, and thediluent should be first rendered isotonic. The aqueous solutions aresuitable for intravenous injection purposes while the oily solutions aresuitable for intra-articular, intra-muscular and subcutaneous injectionpurposes. The aforesaid compositions can be readily prepared understerile conditions following well known standard pharmaceuticaltechniques by persons skilled in the art.

The compounds of formula (I) may also be administered in the form ofsuppositories for rectal or vaginal administration of the activeingredient. These compositions can be prepared by mixing the activeingredient with a suitable non-irritating excipient which is solid atroom temperature (for example, 10° C. to 32° C.) but liquid at therectal temperature and will melt in the rectum or vagina to release theactive ingredient. Such materials are polyethylene glycols, cocoabutter, suppository and wax.

For buccal administration the composition may take the form of tabletsor lozenges formulated in conventional manner.

For transdermal and topical administration, the dosage forms willinclude ointments, pastes, creams, lotions, gels, powders, solutions,sprays and inhalants. Transdermal patches may be prepared followingstandard drug delivery techniques and applied to the skin of a mammal,preferably a human or a dog, to be treated. Ophthalmic solutions, eardrops, eye ointments, powders can also be used as a medium of providingtherapeutic dosages to the patients as will be necessary.

The ointments, pastes, creams and gels may, in addition to the activeingredient, contain excipients like animal and vegetable fats, oils,waxes, paraffins, starch tragacanth, cellulose derivatives, polyethyleneglycols, silicones, bentonites, silicic acid, talc, zinc oxide or theirmixtures.

Powders and sprays may contain, in addition to the active substance,excipients like lactose, talc, silicic acid, aluminium hydroxide,calcium silicates and polyamide powder, or their mixtures. Sprays willadditionally contain propellants like chlorofluorohydrocarbons.

The compounds of the present invention have been tested for theirbiological activities by carrageenan foot pad edema test in male as wellas female Wistar rats according to standard protocol described inliterature (Winter et. al, Proc. Soc. Exp. Biol. Med., 111, 544, (1962);Otterness and Bliven, Laboratory Models for Testing NSAIDS, inNon-Steroidal Anti-inflammatory Drugs, (J. Lombardino, ed. 1985)). Theprotocol followed was as described below:

Wistar rats obtained from the Experimental Animal Facility of ZydusResearch. Centre. Animals were housed in an environmentally controlledrooms with food and water available ad-libitum. All the experimentalprotocols were approved by the Institutional Animal Ethics Committee.Animals were divided into different groups, each group comprising offive-six animals. After an overnight fast, animals of the control groupreceived vehicle only by oral gavage whereas animals of the other groupsreceived different doses of the test substance(s). Each rat receivedsame volume of the formulation i.e. 2 ml/kg on body weight basis. Onehour after administration of the vehicle or test substance, all theanimals received sub-planter injection of carrageenan (1% w/v insaline). Paw volume was measured at 0, 1, 3 and 5 hour after carrageenaninjection. Anti-inflammatory activity, expressed as % Inhibition in pawswelling was calculated by measuring change in paw volume at differenttime intervals after carrageenan injection vs corresponding 0 hr valuesusing the following formula.

${\%\mspace{14mu}{inhibition}} = {\frac{( {{PVC} - {PVT}} )}{PVC} \times 100}$Where

-   PVC=Average change in Paw volume of control animals-   PVT=Average change in Paw volume of treated animals.

The compounds of the present invention inhibited 10%-95% rat paw edemaat a dose of 30 mg/kg. The compounds of the present invention possessanalgesic property and is effective in neuropathy pain. The compounds ofthe present invention inhibit the COX-1 and COX-2 coenzymes to varyingextents as found by human whole blood assay (C. Brideau, S. Kargman, S.Liu; Inflammation Research, 45, 68-74 (1996))

The inhibitory activities of representative compounds of the presentinvention are given in the following table:

Dose % Inhibition of paw edema Sl. No. Compound No. (mg/kg) 1 hour 3hour 1. 179 30 54 41 2. 171 30 50 25 3. 154 30 46 47 4. 97 30 13 36 5.153 30 42 43 6. 158 30 44 26 7. 187 30 33 29 8. 112 30 57 40 9.Celecoxib 30 33 26

The invention is explained in detail by the examples given below, whichare provided by way of illustration only and therefore should not beconstrued to limit the scope of the invention.

1H NMR spectral data given in the tables (vide infra) are are recordedusing a 300 MHz spectrometer (Bruker AVANCE-300) and reported in δscale. Until and otherwise mentioned the solvent used for NMR is CDCl₃Using Tetramethyl silane as the internal standard.

Preparation 15-(3-Fluoro-4-methoxyphenyl)-1-(4-methylsulfanylphenyl)-3-trifluoromethyl-1H-pyrazole(Compound No. 14)

Step 1: Preparation of N-tert-butoxycarbonyl-N-(4-methylsulfanyl)phenylhydrazine

A mixture of 4-methylsulfanyliodobenzene (10 g), tert-butylcarbazate(5.2 g), cesium carbonate (18.2 g), copper iodide (80 rag) and1,10-phenanthroline (576 mg) in DMF (30 mL) was stirred at 90° C. for 18h under nitrogen atmosphere. The reaction mixture was chromatographedover silicagel, using 5% ethyl acetate in petroleum ether as eluent toafford 6.2 g of product as a thick liquid.

Step 2: Preparation of5-(3-fluoro-4-methoxyphenyl)-1-(4-methylsulfanylphenyl)-3-trifluoromethyl-1H-pyrazole

A mixture of 1-(3-fluoro-4-methoxyphenyl)-4,4,4-trifluorobutane-1,3-dione (1.0 g) andN-tert-butoxycarbonyl-N-(4-methylthio)phenyl hydrazine (0.9 g) (obtainedin step 1 above) in ethanolic HCl (25 mL, 12%) was refluxed for 24 h.Solvent was evaporated under reduced pressure. Water (50 mL) was addedto the residue and extracted with diethyl ether (3×50 mL). The organicextract was washed with water (2×50 mL), brine (50 mL), dried oversodium sulphate and evaporated under reduced pressure. The productobtained was chromatographed over silicagel, using 2% ethyl acetate inpetroleum ether as eluent to afford 820 mg of product as a thick liquid.

In like manner the following compounds in table 1 were preparedfollowing the procedure described above:

TABLE 1

X₂ X₁ R₄ R₃ Mol. Wt % Yield 1. H H CF₃

Mol. Wt. = 352 % Yield = 34 ¹H: 2.49(3H, s), 6.7(1H, s), 7.0(2H, t,J=8.7Hz), 7.2(6H, m). 2. H H CF₃

Mol. Wt. = 368.5 % Yield = 62 ¹H: 2.5(3H, s), 6.7(1H, s), 7.15(2H, d,J=8.5Hz), 7.2(4H, m), 7.3(2H, d, J=8.5Hz). 3. H H CF₃

Mol. Wt. = 348 % Yield = 50 ¹H: 2.3(3H, s), 2.48(3H, s), 6.7(1H, s),7.1(4H, m), 7.13(3H, m), 7.3(1H, m). 4. H H CF₃

Mol. Wt. = 364 % Yield = 67 ¹H: 2.4(3H, s), 3.8(3H, s), 6.67(1H, s),6.8(2H, d, J=8.8Hz), 7.1(2H, d, J=8.8Hz), 7.2(4H, m). 5. H H CF₃

Mol. Wt. = 392 % Yield = 46 ¹H: 1.0(3H, t, J=5.7Hz), 1.8(2H, m), 2.4(3H,s), 3.9(2H, t, J=6.5Hz), 6.6(1H, s), 6.8(2H, d, J=6.7Hz), 7.1(2H, d,J=6.6Hz), 7.2(4H, d, J=2.3Hz). 6 H H CF₃

Mol. Wt. = 378 % Yield = 82 ¹H: 1.4(3H, t, J=6.9Hz), 2.4(3H, s), 4.0(2H,q, J=6.9Hz), 6.6(1H, s), 6.8(2H, d, J=8.7Hz), 7.1(2H, d, J=8.7Hz),7.2(4H, m). 7. H H CF₃

Mol. Wt. = 392 % Yield = 69 ¹H: 1.3(6H, d, J=6.0Hz), 2.48(3H, s),4.5(1H, m), 6.6(1H, s), 6.8(2H, d, J=6.6Hz), 7.1(2H, d, J=8.7Hz),7.2(4H, m). 8. H H CF₃

Mol. Wt. = 386.5 % Yield = 50 ¹H: 2.5(3H, s), 6.7(1H, s), 7.1(2H, m),7.2(3H, m), 7.3(2H, dd, J=6.8 & 2.2Hz). 9. H H CF₃

Mol. Wt. = 370 % Yield = 88 ¹H: 2.5(3H, s), 6.7(1H, s), 6.9-7.25(7H,complex). 10. H H CF₃

Mol. Wt. = 366 % Yield = 53 ¹H: 2.2(3H, s), 2.4(3H, s), 6.7(1H, s),6.9(2H, d, J=7.4Hz), 7.1(1H, d, J=7.2Hz), 7.2(4H, m). 11. H H CF₃

Mol. Wt. = 378 % Yield = 58 ¹H: 1.57(3H, s), 2.49(3H, s), 3.9(3H, s),6.7(1H, s), 6.8(1H, d, J=8.7Hz), 6.9(1H, dd, J=2.1 & 8.7Hz), 7.2(4H, m),7.3(1H, d, J=2.1Hz). 12. H H CF₃

Mol. Wt. = 398.5 % Yield = 57 ¹H: 2.49(3H, s), 3.9(3H, s), 6.7(1H, s),6.8(1H, d, J=8.7Hz), 6.9-7.0(1H, dd, J=2.4 & 8.7Hz), 7.2(4H, m), 7.3(1H,d, J=2.4Hz). 13. H H CF₃

Mol. Wt = 443 % Yield = 55 ¹H: 2.49(3H, s), 3.9(3H, s), 6.7(1H, s),6.8(1H, d, J=7.8Hz), 7.0(1H, dd, J=2.1 & 8.5Hz), 7.2(4H, m), 7.5(1H, d,J=2.6Hz). 14. H H CF₃

Mol. Wt. = 382 % Yield = 56.5 ¹H: 2.49(3H, s), 3.9(3H, s), 6.7(1H, s),6.8-6.9(3H, m), 7.2(4H, m). 15. H H CF₃

Mol. Wt. = 378 % Yield = 50.3 ¹H: 2.2(3H, s), 2.48(3H, s), 3.6(3H, s),6.6(1H, s), 6.7(2H, m), 7.0(1H, d, J=7.5Hz), 7.2(4H, m). 16. H F CF₃

Mol. Wt. = 382 % Yield = 74 ¹H: 2.8(3H, s), 3.8(3H, s), 6.7(1H, s),6.8(2H, dd, J=8.8 & 2.14Hz), 6.9(2H, dd, J = 10.4 & 2.01Hz), 7.15(2H,dd, J=8.85 & 2.1Hz), 7.4(1H, t, J=8.0Hz). 17. F H CF₃

Mol. Wt. = 382 % Yield = 66 ¹H: 2.4(3H, s), 3.8(3H, s), 6.67(1H, s),6.8(2H, d, J=8.8Hz), 7.1(2H, m), 7.17(3H, m). 18. H H CF₃

Mol. Wt. = 334 % Yield = 59 ¹H: 2.48(3H, s), 6.7(1H, s), 7.23(4H, m),7.3(5H, m). 19. H H CH₃

Mol. Wt. = 310 % Yield = 42.6 ¹H: 2.23(3H, s), 2.46(3H, s), 3.74(3H, s),6.3(H, s), 6.9(2H, d, J=8.8Hz), 7.1(4H, m), 7.25(2H, d, J=8.67Hz). 20. HH CF₃

Mol. Wt. = 379 % Yield = 77 ¹H: 2.5(3H, s), 6.8(1H, s), 7.2(4H, m),7.4(2H, d, J=8.9Hz), 8.2(2H, d, J=8.9Hz). 21. H H CF₃

Mol. Wt. = 364 % Yield = 71 ¹H: 2.48(3H, s), 3.7(3H, s), 6.7-6.8(3H, m),6.9(1H, m), 7.3(5H, m). 22. H H CF₃

Mol. Wt. = 400 % Yield = 73.6 ¹H: 2.5(3H, s), 4.0(3H, s), 6.7(1H, s),6.79(2H, d, −J=8.6Hz), 7.24(4H, m). 23. H H CF₃

Mol. Wt. = 380 % Yield = 98.5 ¹H: 2.5(3H, s), 3.9(3H, s), 5.7(1H, s,—OH), 6.4-6.8(4H, m), 7.1-7.2(4H, m). 24. H H COOH

Mol. Wt. = 340 % Yield = 90 ¹H: 2.49(3H, s), 3.82(3H, s), 6.8(2H, d,J=8.76Hz), 7.0(1H, s), 7.1(2H, d, J=8.76Hz), 7.26(4H, m) 25. H H CH₂OH

Mol. Wt. = 326 % Yield = 85.5 ¹H: 2.0(1H, t, OH), 2.48(3H, s), 3.8(3H,s), 4.8(2H, m), 6.4(1H, s), 6.8(2H, dd, J=8.8 & 3.5Hz), 7.1(2H, d,J=8.7Hz), 7.14-7.3(4H, m). 26. H H CF₃

Mol. Wt. = 394 % Yield = 53 ¹H: 2.48(3H, s), 3.98(2H, m), 4.0(2H, m),6.68(1H, s), 6.88(2H, d, J=8.85Hz), 7.1(2H, d, J=8.9Hz), 7.2(4H, m) 27.H H CF₃

Mol. Wt. = 335 % Yield = 25.9 ¹H: 2.55(3H, s), 7.18(1H, s), 7.3(2H, dd,J=6.7 & 2.1Hz), 7.4(2H, d, J=8.6Hz), 7.7(2H, dd, J=4.5 & 1.5Hz), 8.7(2H,dd, J=4.6 & 1.5Hz). 28. H H CF₃

Mol. Wt. = 335 % Yield = 61.3 ¹H: 2.54(3H, s), 6.8(1H, s), 7.2(4H, m),7.4(1H, m), 8.2(1H, m), 8.5(1H, d, J=2.0Hz), 9.0(1H, d, J=1.5Hz). 29. HH CF₃

Mol. Wt. = 335 % Yield = 27.8 ¹H: 2.54(3H, s), 7.3(1H, dd, J=6.0 &1.0Hz), 7.35(2H, d, J=8.6Hz), 7.48(3H, m), 7.7(1H, m), 8.0(1H, d,J=7.9Hz), 8.6(1H, m). 30. H H CF₃

Mol. Wt. = 340 % Yield = 45 ¹H: 2.54(3H, s), 6.7(1H, s), 6.8(1H, dd,J=3.57 & 1.05Hz), 6.9(1H, dd, J=5.0 & 3.6Hz), 7.28(4H, m), 7.33(1H, dd,J=5.0 & 1.0Hz).

Preparation 25-(3-Fluoro-4-methoxyphenyl)-1-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-pyrazole(Compound No. 44)

To a solution of5-(3-fluoro-4-methoxyphenyl)-1-(4-methylsulfanylphenyl)-3-trifluoromethyl-1H-pyrazole(compound No. 14) (790 mg) in chloroform (25 mL), m-chloroperbenzoicacid (55-75%, 464 mg) was added in one portion at −40° C. and stirred atthe same temperature for one hour. The reaction mixture was diluted withchloroform (50 mL), washed with saturated solution of aqueous sodiumbicarbonate (30 mL), water (2×30 mL), dried over calcium chloride andevaporated under reduced pressure. The product obtained waschromatographed over silicagel using 7:3 ethyl acetate: petroleum etheras eluent to afford 600 mg of product as a thick liquid.

In like manner compounds in the table 2 were prepared following theprocedure described above:

TABLE 2 X₂ X₁ R₄ R₃ Mol. Wt % Yield 31. H H CF₃

Mol. Wt. = 368 % Yield = 59 ¹H: 2.7(3H, s), 6.7(1H, s), 7.0(2H, t,J=8.7Hz), 7.2(2H, m), 7.4(2H, d, J=8.7Hz), 7.6(2H, d, J=8.7Hz). 32. H HCF₃

Mol. Wt. = 384.5 % Yield = 53 ¹H: 2.7(3H, s), 6.7(1H, s), 7.1(2H, d,J=8.5Hz), 7.3(2H, d, J=8.5Hz), 7.4(2H, d, J=6.4Hz), 7.6(2H, d, J=8.6Hz).33. H H CF₃

Mol. Wt. = 364 % Yield = 70 ¹H: 2.3(3H, s), 2.7(3H, s), 6.7(1H, s),7.11(2H, d, J=8.1Hz), 7.16(2H, d, J=8.1Hz), 7.49(2H, d, J=8.5Hz),7.6(2H, d, J=8.5Hz). 34. H H CF₃

Mol. Wt. = 380 % Yield = 63 ¹H: 2.7(3H, s), 3.8(3H, s), 6.7(1H, s),6.8(2H, d, J=8.7Hz), 7.1(2H, d, J=8.7Hz), 7.5(2H, d, J=8.5Hz), 7.6(2H,d, J=8.9Hz). 35. H H CF₃

Mol. Wt. = 408 % Yield = 87 ¹H: 1.0(3H, t, J=7.4Hz), 1.8(2H, m), 2.7(3H,s), 3.9(2H, t, J=6.5Hz), 6.7(1H, s), 6.8(2H, d, J=6.7Hz), 7.1(2H, d,J=6.7Hz), 7.4(2H, d, J=6.6Hz), 7.6(2H, d, J=6.6Hz). 36. H H CF₃

Mol. Wt. = 394 % Yield = 84 ¹H: 1.4(3H, t, J=6.9Hz), 2.7(3H, s), 4.0(2H,q, J=6.9Hz), 6.7(1H, s), 6.8(2H, d, J=8.8Hz), 7.1(2H, d, J=8.8Hz),7.5(2H, d, J=8.6Hz), 7.6(2H, d, J=8.6Hz). 37. H H CF₃

Mol. Wt. = 408 % Yield = 68 ¹H: 1.3(6H, d, J=6.1Hz), 2.7(3H, s), 4.5(1H,m), 6.7(1H, s), 6.8(2H, d, J=8.9Hz), 7.1(2H, d, J=9.0Hz), 7.5(2H, d,J=8.7Hz), 7.6(2H, d, J=8.9Hz). 38 H H CF₃

Mol. Wt. = 402.5 % Yield = 64 ¹H: 2.7(3H, s), 6.7(1H, s), 7.1(2H, m),7.3(1H, dd, J=8.9 & 2.1Hz), 7.5(2H, d, J=8.67Hz), 7.7(2H, d, J=8.7Hz).39. H H CF₃

Mol. Wt. = 386 % Yield = 65 ¹H: 2.7(3H, s), 6.78(1H, s), 7.1(3H, m),7.5(2H, d, J=8.6Hz), 7.7(2H, d, J=8.3Hz). 40. H H CF₃

Mol. Wt. = 382 % Yield = 65 ¹H: 2.2(3H, s), 2.7(3H, s), 6.7(1H, s),6.9(2H, m), 7.1(1H, m), 7.4(2H, d, J=8.7Hz), 7.6(2H, d, J=8.6Hz). 41. HH CF₃

Mol. Wt. = 394 % Yield = 78 ¹H: 2.1(3H, s), 2.7(3H, s), 3.8(3H, s),6.7(1H, s), 6.73(1H, d, J=8.3Hz), 6.9(1H, dd, J=2.1 & 8.1Hz), 7.0(1H, d,J=2.4Hz), 7.5(2H, d, J=8.5Hz), 7.6(2H, d, J=8.3Hz). 42. H H CF₃

Mol. Wt. = 414.5 % Yield = 80.5 ¹H: 2.7(3H, s), 3.9(3H, s), 6.7(1H, s),6.8(1H, d, J=8.5Hz), 7.0(1H, dd, J=2.1 & 8.4Hz), 7.3(1H, d, J=2.4Hz),7.5(2H, d, J=8.5Hz), 7.6(2H, d, J=8.5Hz). 43. H H CF₃

Mol. Wt. = 459 % Yield = 55 ¹H: 2.7(3H, s), 3.9(3H, s), 6.7(1H, s),6.8(1H, d, J=8.5Hz), 7.0(1H, dd, J=2.1 & 8.5Hz), 7.4-7.5(3H, m), 7.6(2H,d, J=8.5Hz). 44. H H CF₃

Mol. Wt. = 398 % Yield = 73 ¹H: 2.7(3H, s), 3.9(3H, s), 6.7(1H, s),6.9(3H, m), 7.4(2H, d, J=8.5Hz), 7.6(2H, d, J=8.5Hz). 45. H H CF₃

Mol. Wt. = 394 % Yield = 71 ¹H: 2.2(3H, s), 2.7(3H, s), 3.6(3H, s),6.6(1H, d, J=1.2Hz), 6.6-6.7(1H, dd, J=1.4 & 7.6Hz), 6.7(1H, s),7.0-7.1(1H, d, J=7.6Hz), 7.5(2H, d, J=8.6Hz), 7.6(2H, d, J=8.6Hz). 46. HF CF₃

Mol. Wt. = 398 % Yield = 51 ¹H: 2.7(3H, s), 3.8(3H, s), 6.7(1H, s),6.8(2H, d, J=8.8Hz), 7.1(2H, d, J=8.8Hz), 7.4(2H, m), 7.6(1H, m). 47. FH CF₃

Mol. Wt. = 398 % Yield = 77 ¹H: 2.8(3H, s), 3.8(3H, s), 6.7(1H, s),6.9(2H, d, J=8.8Hz), 7.1(2H, d, J=8.8Hz), 7.2(2H, m), 7.8(1H, t,J=7.8Hz). 48. H H CF₃

Mol. Wt. = 350 % Yield = 36 ¹H: 2.7(3H, s), 6.7(1H, s), 7.2(2H, d,J=8.5Hz), 7.4(3H, m), 7.5(2H, d, J=8.5Hz), 7.6(2H, d, J=8.5Hz). 49. H HCH₃

Mol. Wt. = 326 % Yield = 80 ¹H: 2.37(3H, s), 2.7(3H, s), 3.8(3H, s),6.27(1H, s), 6.8(2H, d, J=8.8Hz), 7.1(2H, d, J=8.8Hz), 7.46(2H, d,J=8.6Hz), 7.6(2H, d, J=8.6Hz). 50. H H CF₃

Mol. Wt. = 395 % Yield = 82 ¹H: 2.8(3H, s), 6.9(1H, s), 7.2-7.4(4H, m),7.7(2H, d, J=8.5Hz), 8.25(2H, d, J=8.8Hz). 51. H H CF₃

Mol. Wt. = 380 % Yield = 68 ¹H: 2.7(3H, s), 3.7(3H, s), 6.8(3H, m),6.9(1H, m), 7.3(1H, m), 7.5(2H, d, J=8.5Hz), 7.7(2H, d, J=8.5Hz). 52. HH CF₃

Mol. Wt. = 416 % Yield = 49 ¹H: 2.7(3H, s), 4.0(3H, s), 6.79(3H, m),7.5(2H, d, J=8.64Hz), 7.7(2H, d, J=8.6Hz). 53. H H CF₃

Mol. Wt. = 396 % Yield = 83 ¹H: 2.7(3H, s), 3.9(3H, s), 5.7(1H, s),6.7(2H, m), 6.8(2H, m), 7.5(2H, d, J=8.6Hz), 7.67(2H, d, J=8.6Hz). 54. HH COOH

Mol. Wt. = 356 % Yield = 63 ¹H: 2.7(3H, s), 3.8(3H, s), 6.8(2H, d,J=8.4Hz), 6.9(1H, s), 7.16(2H, d, J=8.34Hz), 7.5(2H, d, J=8.3Hz),7.65(2H, d, J=8.3Hz0). 55. H H CH₂OH

Mol. Wt. = 342 % Yield = 80 ¹H: 2.7(3H, s), 3.8(3H, s), 4.79(2H, s),6.5(1H, s), 6.87(2H, d, J=8.7Hz), 7.16(2H, d, J=8.7Hz), 7.47(2H, d,J=8.5Hz), 7.6(2H, d, J=8.5Hz). 56. H H CF₃

Mol. Wt. = 410 % Yield = 70 ¹H: 2.74(3H, s), 3.98(2H, m), 4.1(2H, dd,J=5.4 & 4.0Hz), 6.7(1H, s), 6.9(2H, dd, J=8.8 & 2.0Hz), 7.1(2H, dd,J=8.8 & 2.0Hz), 7.5(2H, dd, J=8.9 & 2.1Hz), 7.6(2H, dd, J=6.6 & 1.9Hz)57. H H CF₃

Mol. Wt. = 351 % Yield = 25.9 ¹H: 2.89(3H, s), 7.66(1H, s), 7.84(2H, d,J=8.55Hz), 7.9(4H, m), 8.6(2H, d, J=5.7Hz). 58. H H CF₃

Mol. Wt. = 351 % Yield = 61.3 ¹H: 2.8(3H, s), 7.1(1H, s), 7.4(1H, m),7.75(2H, d, J=8.58Hz), 7.8(2H, d, J=8.64Hz), 8.1(1H, m), 8.6(1H, dd,J=4.74 & 1.2Hz), 9.0(1H, d, J=1.53Hz). 59. H H CF₃

Mol. Wt. = 351 % Yield = 27.8 ¹H: 2.8(3H, s), 7.3(1H, dd, J=9.0 &1.2Hz), 7.54(1H, s), 7.8(5H, m), 8.0(1H, d, J=8.0Hz), 8.67(1H, d,J=4.5Hz). 60. H H CF₃

Mol. Wt. = 356 % Yield = 54 ¹H: 2.76(3H, s), 6.8(1H, s), 6.9(1H, dd,J=3.7 & 1.05Hz), 7.0(1H, dd, J=5.0 & 3.6Hz), 7.4(1H, dd, J=5.1 & 1.1Hz),7.6(2H, dd, J=8.5 & 1.9Hz), 7.7(2H, dd, J=8.5 & 1.9Hz).

Preparation 35-(3-Fluoro-4-methoxyphenyl)-1-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole(Compound No. 74)

To a solution of5-(3-fluoro-4-methoxyphenyl)-1-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-pyrazole(Compound No. 44) (570 mg) in chloroform (25 mL) were added sodium azide(186 mg) followed by concentrated sulfuric acid (0.14 mL) at 0° C. andstirred at 40° C. for 18 h. An equal amount of sodium azide and sulfuricacid that were added earlier was added every two hours for four timesand stirred for further four hours thereafter at 40° C. The reactionmixture was cooled to 20° C., diluted with chloroform (50 mL), washedwith saturated aqueous solution of sodium bicarbonate (2×50 mL), water(50 mL), dried over calcium chloride and evaporated under reducedpressure to afford the product (500 mg) as a thick liquid.

In like manner compounds in the table 3 were prepared following theprocedure described above

TABLE 3

X₂ X₁ R₄ R₃ Mol. Wt Yield 61. H H CF₃

Mol. Wt. = 383 % Yield = 36 ¹H, CD₃OD: 3.8(3H, s), 6.9(1H, s), 7.0(2H,t, J=8.7Hz), 7.2(2H, m), 7.6(2H, d, J=8.9Hz), 8.1(2H, d, J=8.9Hz). 62. HH CF₃

Mol. Wt. = 399.5 % Yield = 72 ¹H, CD₃OD: 3.8(3H, s), 7.0(1H, s), 7.3(2H,d, J=8.7Hz), 7.4(2H, d, J=8.6Hz), 7.7(2H, d, J=8.9Hz), 8.2(2H, d,J=9.0Hz). 63. H H CF₃

Mol. Wt. = 379 % Yield = 71 ¹H: 2.3(3H, s), 3.1(3H, s), 6.7(1H, s),7.1(2H, d, J=8.1Hz), 7.18(2H, d, J=8.1Hz), 7.5(2H, d, J=8.5Hz), 7.9(2H,d, J=8.5Hz). 64. H H CF₃

Mol. Wt. = 395 % Yield = 51 ¹H, CD₃OD: 3.8(3H, s), 3.9(3H, s), 6.9(1H,s), 6.9(2H, d, J=8.7Hz), 7.2(2H, d, J=9.0Hz), 7.7(2H, d, J=9.0Hz),8.2(2H, d, J=9.1Hz). 65. H H CF₃

Mol. Wt. = 423 % Yield = 33 ¹H, dMSO-d₆: 1.0(3H, t, J=7.4Hz), 1.8(2H,m), 3.8(3H, s), 3.9(2H, t, J=6.4Hz), 6.9(2H, d, J=8.7Hz), 6.9(1H, s),7.2(2H, d, J=8.7Hz), 7.7(2H, d, J=8.8Hz), 8.19(2H, d, J=8.8Hz). 66. H HCF₃

Mol. Wt. = 409 % Yield = 22 ¹H, CD₃OD: 1.2(3H, t, J=6.9Hz), 3.7(3H, s),3.9(2H, q, J=6.9Hz), 6.8(1H, s), 6.8(2H, d, J=8.8Hz), 7.1(2H, d,J=8.8Hz), 7.6(2H, d, J=8.9Hz), 8.1(2H, d, J=8.9Hz). 67. H H CF₃

Mol. Wt. = 381 % Yield = 66 ¹H, CD₃OD: 3.8(3H, s), 6.7(2H, d, J=8.6Hz),6.8(1H, s), 7.1(2H, d, J=8.6Hz), 7.7(2H, d, J=8.9Hz), 8.2(2H, d,J=8.9Hz). 68. H H CF₃

Mol. Wt. = 417.5 % Yield = 95 ¹H, CD₃OD: 3.89(3H, s), 7.0(1H, s),7.3(2H, d, J=7.7Hz), 7.5(1H, d, J=6.9Hz), 7.8(2H, d, J=8.9Hz), 8.2(2H,m). 69. H H CF₃

Mol. Wt. = 401 % Yield = 96 ¹H, CD₃OD: 3.9(3H, s), 7.0(1H, s), 7.2(1H,m), 7.3(2H, m), 7.8(2H, d, J=8.8Hz), 8.2(2H, d, J=8.8Hz). 70. H H CF₃

Mol. Wt. = 397 % Yield = 47 ¹H, CD₃OD: 2.2(3H, s), 3.7(3H, s), 6.9(1H,s), 7.1(2H, m), 7.3(1H, d, J=7.2Hz), 7.7(2H, d, J=8.9Hz), 8.2(2H, d,J=8.9Hz). 71. H H CF₃

Mol. Wt. = 409 % Yield = 41 ¹H, CD₃OD: 2.1(3H, s), 3.3(3H, s), 3.8(3H,s), 6.9(1H, d, J=8.5Hz), 7.0(1H, dd, J=2.1 & 8.5Hz), 7.1(1H, s), 7.2(1H,d, J=1.52Hz), 7.6(2H, d, J=8.6Hz), 8.0(2H, d, J=8.7Hz). 72. H H CF₃

Mol. Wt. = 429.5 % Yield = 34.5 ¹H, CD₃OD: 3.8(3H, s), 3.9(3H, s),6.9(1H, s), 7.0-7.1(1H, d, J=8.6Hz), 7.2(1H, dd, J=2.1 & 8.2Hz), 7.3(1H,d, J=2.1Hz), 7.7(2H, d, J=8.9Hz), 8.2(2H, d, J=8.9Hz). 73. H H CF₃

Mol. Wt. = 474 % Yield = 56 ¹H, CD₃OD: 3.9(3H, s), 3.92(3H, s), 6.9(1H,s), 7.0(1H, d, J=8.5Hz), 7.2-7.3(1H, dd, J=2.1 & 8.5Hz), 7.5(1H, d,J=2.1Hz), 7.8(2H, d, J=8.9Hz), 8.2(2H, d, J=8.9Hz). 74. H H CF₃

Mol. Wt. = 413 % Yield = 74 ¹H, CD₃OD: 3.89(3H, s), 3.9(3H, s), 6.9(1H,s), 7.1(3H, m), 7.7(2H, d, J=8.8Hz), 8.2(2H, d, J=8.5Hz). 75. H H CF₃

Mol. Wt. = 409 % Yield = 40 ¹H: 2.2(3H, s), 2.7(3H, s), 3.6(3H, s),6.6(1H, d, J=1.2Hz), 6.6-6.7(1H, dd, J=1.4 & 7.6Hz), 6.7(1H, s),7.0-7.1(1H, d, J=7.6Hz), 7.5(2H, d, J=8.6Hz), 7.6(2H, d, J=8.6Hz). 76. HF CF₃

Mol. Wt. = 413 % Yield = 94 ¹H: 3.1(3H, s), 3.8(3H, s), 6.7(1H, s),6.8(2H, dd, J=2.0 & 8.8Hz), 7.1(2H, dd, J=2.0 & 8.8Hz), 7.7(2H, m),7.9(1H, m). 77. F H CF₃

Mol. Wt. = 413 % Yield = 25 ¹H: 3.2(3H, s), 3.8(3H, s), 6.7(1H, s),6.9(2H, d, J=8.8Hz), 7.1(3H, m), 7.3(1H, dd, J=1.9 & 10.4Hz), 7.9(1H, d,J=8.4Hz). 78. H H CF₃

Mol. Wt. = 365 % Yield = 32 ¹H, CD₃OD: 3.8(3H, s), 7.0(1H, s),7.3-7.4(5H, m), 7.7(2H, d, J=8.7Hz), 8.1(2H, d, J=8.8Hz). 79. H H CH₃

Mol. Wt. = 341 % Yield = 93 ¹H, CD₃OD: 2.35(3H, s), 3.8(3H, s), 3.89(3H,s), 6.4(1H, s), 6.9(2H, d, J=8.8Hz), 7.2(2H, d, J=8.8Hz), 7.7(2H, d,J=8.9Hz), 8.1(2H, d, J=8.9Hz). 80. H H CF₃

Mol. Wt. = 410 % Yield = 92 ¹H, CD₃OD: 3.9(3H, s), 7.2(1H, s), 7.6(2H,d, J=8.9Hz), 7.8(2H, d, J=8.9Hz), 8.2(4H, m), 81. H H CF₃

Mol. Wt. = 395 % Yield = 84 ¹H, CD₃OD: 3.7(3H, s), 3.9(3H, s), 6.9(2H,m), 7.0(2H, m), 7.3(1H, t, J=7.9Hz), 7.8(2H, d, J=8.9Hz), 8.2(2H, d,J=8.9Hz). 82. H H CF₃

Mol. Wt. = 431 % Yield = 90 ¹H, CD₃OD: 3.9(3H, s), 4.0(3H, s), 7.02(1H,s), 7.06(2H, d, J=2.7Hz), 7.8(2H, d, J=8.9Hz), 8.2(2H, d, J=8.9Hz). 83.H H CF₃

Mol. Wt. = 411 % Yield = 46 ¹H, CD₃OD: 3.86(3H, s), 3.91(3H, s), 6.7(1H,d, J=2.07Hz), 6.8(1H, dd, J=8.25 & 2.07Hz), 6.9(2H, m), 7.8(2H, d,J=8.85Hz), 8.2(2H, d, J=8.85Hz). 84. H H COOH

Mol. Wt. = 371 % Yield = 56 ¹H, dMSO-d₆: 3.09(3H, s), 3.75(3H, s),6.9(2H, d, J=8.7Hz), 7.0(1H, s), 7.2(2H, d, J=8.7Hz), 7.5(2H, d,J=8.5Hz), 7.9(2H, d, J=8.5Hz). 85. H H CH₂OH

Mol. Wt. = 357 % Yield = 46 ¹H, CD₃OD: 3.8(3H, s), 3.9(3H, s), 4.67(2H,s), 6.6(1H, s), 6.95(2H, d, J=8.8Hz), 7.23(2H, d, J=8.8Hz), 7.7(2H, d,J=8.99Hz), 8.17(2H, d, J=8.99Hz). 86. H H CH₂OSO₃H

Mol. Wt. = 437 % Yield = 28 ¹H, dMSO-d₆: 3.77(3H, s), 3.86(3H, s),4.87(2H, s), 6.6(1H, s), 6.98(2H, d, J=8.7Hz), 7.2(2H, d, J=8.7Hz),7.65(2H, d, J=8.8Hz), 8.1(2H, d, J=8.8Hz). 87. H H CF₃

Mol. Wt. = 425 % Yield = 25 ¹H: 1.99(1H, t, OH), 2.73(1H, br, NH),3.1(3H, s), 4.0(2H, m), 4.1(2H, m), 6.7(1H, s), 6.9(2H, dd, J=8.7 &2.1Hz), 7.15(2H, dd, J=8.8 & 2.1Hz), 7.5(2H, dd, J=8.7 & 2.2Hz), 8.0(2H,dd, J=8.7 & 1.9Hz). 88 H H CF₃

Mol. Wt. = 366 % Yield = 78.3 ¹H: 3.18(3H, s), 7.27(1H, s), 7.75(2H, dd,J=4.5 & 1.6Hz), 7.8(2H, d, J=8.5Hz), 8.2(2H, d, J=8.7Hz), 8.7(2H, dd,J=4.5 & 1.5Hz). 89. H H CF₃

Mol. Wt. = 366 % Yield = 86.5 ¹H: 3.18(3H, s), 7.23(1H, s), 7.4(1H, m),7.8(2H, d, J=8.61Hz), 8.1(3H, m), 8.6(1H, d, J=4.7Hz), 9.0(1H, s). 90. HH CF₃

Mol. Wt. = 366 % Yield = 88.8 ¹H: 3.1(3H, s), 7.3(1H, m), 7.5(1H, s),7.7-7.8(3H, m), 8.0(1H, d, J=7.9Hz), 8.2(2H, d, J= 8.64Hz), 8.69(1H, d,J=4.68Hz). 91. H H CF₃

Mol. Wt. = 423 % Yield = 82 ¹H: 1.3(6H, d, J=6.0Hz), 3.1(3H, s), 4.6(1H,m), 6.7(1H, s), 6.85(2H, d, J=8.6Hz), 7.1(2H, d, J=8.67Hz), 7.5(2H, d,J=8.52Hz), 8.0(2H, d, J=8.55Hz). 92. H H CF₃

Mol. Wt. = 371 % Yield = 14 ¹H, CD₃OD: 3.8(3H, s), 7.1(3H, m), 7.6(1H,dd, J=4.8 & 1.4Hz), 7.8(2H, d, J=8.7Hz), 8.2(2H, d, J=8.7Hz).

Preparation 4 5-Chloro-3-(4-methylsulfanylphenyl)-[2,3′]bipyridinyl(Compound No. 93)

A mixture of 3-[2-(4-methylsulfanylphenyl)acetyl]pyridine (0.9 g),2-chloromalondialdehyde (0.98 g) and ammonium acetate (1.85 g) washeated to 130° C. for 16 h. while distilling off the acetic acid formed.The reaction mixture was cooled, basified with aqueous sodium carbonate,extracted with dichloromethane (2×100 mL) and dried over anhydroussodium sulfate. The combined organic layer was heated with activatedcharcoal, filtered, and evaporated under reduced pressure. The crudeproduct was chromatographed over silicagel

using 10% to 50% ethyl acetate in petroleum ether as eluent yielding 280mg of product as a dark yellow solid.

In like manner compounds in the table 4 were prepared following theprocedure described above.

TABLE 4

Com- pound No. R₃ Molecular Weight % yield 93.

Mol. Wt. = 312.5 % Yield = 24.21 ¹H: 2.48(3H, s), 7.06-7.08(2H, d,J=8.4Hz), 7.15-7.18(2H, d, J=8.4Hz), 7.20-7.25(1H, m), 7.67-7.69(1H, m),7.73-7.74(1H, d, J=2.3Hz), 8.50-8.52(1H, dd, J=3.2 & 4.8Hz), 8.57(1H, d,J=1.64Hz), 8.6(1H, d, J=2.35Hz) 94.

Mol. Wt. = 326.5 % Yield = 26.24 ¹H: 2.48(3H, s), 2.53(3H, s),7.05-7.09(3H, m), 7.19-7.16(2H, d, J=6.39Hz), 7.59-7.55(1H, d,J=8.04Hz), 7.71-7.70(1H, d, J=2.34Hz), 8.45-8.44(1H, d, J=2.25Hz),8.64-8.63(1H, d, J=2.37Hz)

The sulfides obtained as per the procedure described in preparation 4were converted to the corresponding sulfoxides by a procedure similar tothat described in preparation 2 above.

TABLE 5

Com- pound No. R₃ Molecular Weight % yield 95.

Mol. Wt. = 328.5 % Yield = 44.16 ¹H: 2.76(3H, s), 7.28-7.30(1H, d,J=4.95Hz), 7.34-7.37(2H, d, J=8.3Hz), 7.61-7.64(2H, d, J=8.3Hz),7.73-7.76(1H, d, J=8Hz), 7.78-7.79(1H, d, J=2.34Hz), 8.54(2H, s),8.72-8.73(1H, d, J=2.3Hz) 96.

Mol. Wt. = 342.5 % Yield = 47 ¹H: 2.54(3H, s), 2.2.76(3H, s),7.06-7.08(1H, d, J=8Hz), 7.34-7.37(2H, d, J=8.37Hz), 7.54-7.57(1H, dd,J=2.3 & 8Hz), 7.6-7.63(2H, d, J=6.4Hz), 7.7(1H, d, J=2.34Hz), 8.4(1H, d,J=2.3Hz), 8.7(1H, d, J=2.3Hz).

The sulfoxides obtained as per the procedure described in Preparation 5were converted to the corresponding sulfoximines by a procedure similarto that described in preparation 3 above.

TABLE 6

Compound No. R₃ Molecular Weight % yield 97.

Mol. Wt. = 343.5 % Yield = 44 ¹H: 2.75(3H, s), 7.22-7.24(1H, m),7.33-7.36(2H, d, J=8.2Hz), 7.60-7.63(2H, d, J=8.2Hz), 7.67-7.7(1H, d,J=8Hz), 7.77-7.78(1H, d, J=2.3Hz), 8.52-8.54(2H, s), 8.72(1H, d,J=2.3Hz) 98.

Mol. Wt. = 357.5 % Yield = 79 ¹H: 2.54(3H, s), 3.14(3H, s),7.10-7.13(1H, d, J=8.04Hz), 7.36-7.39(2H, d, J=8Hz), 7.60-7.64(1H, dd,J=2.3 & 8.04Hz), 7.7(1H, d, J=2.3Hz), 7.96-7.98(2H, d, J=8.5Hz), 8.3(1H,d, J=2Hz), 8.7(1H,d, J=2.4Hz)

The sulfides of general formula given below were prepared according tothe procedures well known in the art (for example as described in WO0181332).

The sulfides of general formula given above were converted to thecorresponding sulfoxides by a procedure similar to that described inpreparation 2 above

TABLE 7

Compound No. X₂ X₁ R₃ Mol. Wt Yield  99. F H

Mol. Wt. = 385 % Yield = 41.1 ¹H: 2.9(3H, s), 5.2(2H, s), 7.05(1H, dd,J=1.5 & 10Hz), 7.2(1H, dd, J=2 & 8.3Hz), 7.3(1H, d, J=1.5 & 8.1Hz),7.4(1H, d, J=8.3Hz), 7.5(1H, d, J=8.4Hz), 7.9(1H, t, J=7.6Hz). 100. F H

Mol. Wt. = 350.5 % Yield = 70 ¹H: 2.9(3H, s), 5.2(2H, s), 7.05(1H, dd,J=1.5 & 10Hz), 7.3-7.4(5H, m), 7.8(1H, t, J=7.5Hz) 101. F H

Mol. Wt. = 316 % Yield = 33.3 ¹H: 2.85(3H, s), 5.2(2H, s), 7.05(1H, dd,J=1.5 & 10Hz), 7.34-7.37(1H, dd, J=1.5 & 8.1Hz), 7.38-7.8(5H, m),7.83-7.89(1H, t, J=7.7Hz). 102. F H

Mol. Wt. = 352 % Yield = 57.4 ¹H: 2.87(3H, s), 5.2(2H, s), 7.03-7.07(1H,dd, J=1.5 & 10Hz), 7.16-7.3(3H, m), 7.34-7.37(1H, dd, J=1.5 & 8.1Hz),7.9(1H, t, J=7.6Hz). 103. F H

Mol. Wt. = 376 % Yield = 66 ¹H: 2.85(3H, s), 3.80(3H, s), 3.9(3H, s),5.15(2H, s), 6.86-6.89(1H, d, J=8.2Hz), 6.96-7.0(2H, m), 7.09-7.14(1H,dd, J=1.5 & 10.3Hz), 7.4(1H, dd, J=1.5 & 8.07Hz), 7.86-7.91(1H, t,J=7.6Hz). 104. F H

Mol. Wt. = 346 % Yield = 71.5 ¹H: 2.86(3H, s), 3.84(3H, s), 5.14(2H, s),6.91-6.95(2H, dd, J=2 & 6.87Hz), 7.08-7.12(1H, dd, J=1.4 & 10.3Hz),7.36-7.39(3H, m), 7.84-7.89(1H, t, J=7.6Hz) 105. F H

Mol. Wt. = 330 % Yield = 35.4 ¹H: 2.39(3H, s), 2.85(3H, s), 5.15(2H, s),7.07-7.1(1H, dd, J=1.5 & 10.35Hz), 7.2-7.32(4H, m), 7.34-7.38(1H, dd,J=1.5 & 8.1Hz), 7.84-7.89(1H, t, J=7.6Hz)

The sulfoxides of table 7 were converted to the correspondingsulfoximines by a procedure similar to that described in preparation 3above.

TABLE 8

Compound No. X₂ X₁ R₃ Mol. Wt % Yield 106. F H

Mol. Wt. = 400 % Yield = 77 ¹H: 3.3(3H, s), 5.18(2H, s), 7.15-7.27(3H,m), 7.7.47-7.5(1H, d, J=8.3Hz), 7.58(1H, d, J=2Hz), 7.97-8.02(1H, t,J=7.6Hz). 107. F H

Mol. Wt. = 365.5 % Yield = 77 ¹H: 3.3(3H, s), 5.17(2H, s), 7.15-7.19(1H,dd, J=1.56 & 10.32Hz), 7.24(1H, d, J=1.6Hz), 7.32-7.42(4H, m),7.95-8.0(1H, t, J=7.8Hz) 108. F H

Mol. Wt. = 331 % Yield = 47 ¹H, dMSO-d₆: 3.30(3H, s), 5.39(2H, s),7.32-7.36(3H, m), 7.42-7.5(4H, m), 7.83-7.88(1H, t, J=7.9Hz). 109. F H

Mol. Wt. = 367 % Yield = 67 ¹H: 3.3(3H, s), 5.17(2H, s), 7.15-7.34(5H,m), 7.97-8.02(1H, t, J=7.7Hz). 110. F H

Mol. Wt. = 391 % Yield = 30 ¹H: 3.3(3H, s), 3.8(3H, s), 3.9(3H, s),5.15(2H, s), 6.85-6.88(1H, d, J=8.3Hz), 6.93-6.96(1H, d, J=2 & 8.3Hz),7.0(1H, d, J=1.5Hz), 7.20-7.24(1H, dd, J=1.5 & 8.1Hz), 7.29-7.32(1H, dd,J=1.5 & 8.1Hz), 7.93-7.98(1H, t, J=7.8Hz). 111. F H

Mol. Wt. = 361 % Yield = 48 ¹H: 3.3(3H, s), 3.85(3H, s), 5.14(2H, s),6.92-6.95(2H, d, J=6.78Hz), 7.18-7.22(1H, dd, J=1.5 & 10.56Hz),7.27-7.30(1H, dd, 1.59 & 8.25Hz), 7.35-7.38(2H, d, J=6.8Hz),7.92-7.98(1H, t, J=7.8Hz) 112. F H

Mol. Wt. = 345 % Yield = 69 ¹H: 2.39(3H, s), 3.28(3H, s), 5.15(2H, s),7.17-7.13(6H, m), 7.91-7.97(1H, t, J=7.8Hz).

Preparation 5 3-(3-Fluorophenyl)-4(4-methylsulfanyl)-3H-thiazol-2-one(Compound No. 113)

Step 1: Preparation of ethyl(3-fluorophenyl) thiocarbamate

A solution of 3-fluoroaniline (4 g) and bis(ethoxythiocarbanyl)sulfide(7.56 g) in 50 mL EtOH was stirred at ambient temperature for 24 h. Thesolvent was evaporated and the residue was triturated with pentaneyielding 4.0 g of product as a light cream solid.

Step 2: Preparation of3-(3-fluorophenyl)-4-hydroxy-4(4-methylsulfanylphenyl)-thiazolidin-2-one

A mixture of ethyl(3-fluorophenyl)thiocarbamate (1 g) (prepared instep 1) and 2-bromo-1-(4-methylsulfanylphenyl)ethanone (1.4 g) in 20 mLof THF was refluxed for 8 h. A slight insoluble material was filtered,the solvent was then evaporated and the residue was taken up indichloromethane. The organic solution was dried over sodium sulfate,evaporated and the residue was crystallized from ether giving 0.8 g ofproduct as a pale yellow solid.

Step 3: Preparation of3-(3-fluorophenyl)-4(4-methylsulfanyl)-3H-thiazol-2-one

To a solution of3-(3-fluorophenyl)-4-hydroxy-4-(4-methylsulfanylphenyl)-thiazolidin-2-one(1 g) (prepared in step 2) in ethanol (50 mL) was added 0.5 mL ofconcentrated HCl and refluxed for 5 h. The reaction mixture was cooledto 25° C. Precipitated solid was filtered, washed with ethanol and driedto yield 0.8 g of product as a pale yellow solid.

In like manner compounds in the table 9 were prepared following theprocedure described above

TABLE 9

Compound No. R₃ Molecular Weight % yield 113.

Mol. Wt. = 317 % Yield = 84 ¹H: 2.45(3H, s), 6.18(1H, s), 6.89-7.09(6H,complex), 7.28-7.31(2H, m). 114.

Mol. Wt. = 368 % Yield = 84 ¹H: 2.46(3H, s), 6.18(1H, s), 6.88-6.92(1H,dd, J=2.43Hz & 8.5Hz), 6.96-6.99(2H, d, J=8.4Hz), 7.09-7.12(2H, d,J=7.5Hz), 7.35(1H, d, J=2.4Hz), 7.37-7.40(1H, d, J=8.6Hz).

The sulfides described above were converted to the correspondingsulfoxides by a procedure similar to that described in preparation 2.

TABLE 10

Compound No. X R₃ Mol. Wt % Yield 115.* O

Mol. Wt. = 368 % Yield = 64.5 ¹H: 2.74(3H, s), 6.9-7.0(1H, d, J=8.6 &2.5Hz), 7.1(1H, s), 7.2(2H, d, J=8.5Hz), 7.4(1H, d, J=2.5Hz), 7.4(1H, d,J=8.6Hz), 7.6(2H, d, J=8.5Hz). 116.* O

Mol. Wt. = 378 % Yield = 73 ¹H: 2.74(3H, s), 7.0(2H, d, J=8.7Hz),7.09(1H, s), 7.2(2H, d, J=8.4Hz), 7.5(2H, d, J=8.7Hz), 7.6(2H, d,J=8.4Hz). 117.* O

Mol. Wt. = 299 % Yield = 28 ¹H: 2.7(3H, s), 7.1(1H, s), 7.2(4H, m),7.4(3H, m), 7.5(2H, d, J=8.5Hz). 118.* O

Mol. Wt. = 317 % Yield = 53 ¹H: 2.7(3H, s), 7.2(3H, m), 7.27(2H, d,J=8.3Hz), 7.3-7.4(2H, m), 7.6(2H, d, J=8.4Hz). 119. S

Mol. Wt. = 333 % Yield = 76 ¹H: 2.7(3H, s), 6.3(1H, s), 6.4-6.9(2H, m),7.0-7.08(2H, m), 7.23-7.36(3H, m), 7.5(2H, d, J=8.2Hz). 120. S

Mol. Wt. = 384 % Yield = 88 ¹H: 2.72(3H, s), 6.3(1H, s), 6.9(1H, dd,J=2.4 & 8.5Hz), 7.2(2H, d, J=8.3Hz), 7.3(1H, d, J=2.4Hz), 7.4(1H, d,J=8.5Hz), 7.5(2H, d, J=8.3Hz). *The corresponding sulfides were preparedaccording to procedures known in the art.

Preparation 64-(4-Methylsulfoximinylphenyl)-3-(3,4-dichlorophenyl)-3H-oxazol-2-one(Compound No. 121)

To a stirred solution of4-(4-methylsulfinylphenyl)-3-(3,4-dichlorophenyl)-3H-oxazol-2-one(Compound no. 115) (1.1 g) in 20 ml of dichloromethane was addedO-mesitylenesulfonyl hydroxylamine (1.12 g) at 25° C. and stirred for 12h. The reaction mixture was basified to pH 11 with 2N NaOH solution,stirred for 30 min and extracted with dichloromethane (3×100 mL), Theorganic extract was dried over anhydrous sodium sulfate and evaporatedunder reduced pressure.

The crude product obtained was chromatographed using 20 to 60% ethylacetate in petroleum ether as eluent to give 670 mg pure product as agum.

In like manner compounds in the table 11 were prepared following theprocedure described above.

TABLE 11 Compound No. X R³ Mol. Wt Yield 121. O

Mol. Wt. = 383 % Yield = 32 ¹H, CD₃OD: 3.6(3H, s), 7.0-7.1(1H, d, J=2.4& 8.6Hz), 7.4-7.5(4H, m), 7.59(1H, s), 8.0(2H, d, J=8.7Hz). 122. O

Mol. Wt. = 393 % Yield = 57.7 ¹H: 3.1(3H, s), 7.0(2H, d, J=6.7Hz),7.09(1H, s), 7.2(2H, d, J=6.2Hz), 7.5(2H, d, J=8.7Hz). 7.9(2H, d, J=8.4Hz). 123. O

Mol. Wt. = 314 % Yield = 47 ¹H, CDCl₃ + DMSO-d₆: 3.2(3H, s), 7.2(2H, d,J=8.1Hz), 7.3(2H, d, J=9.0Hz), 7.4(3H, m), 7.8(2H, d, J=8.5Hz), 8.1(1H,s). 124. O

Mol. Wt. = 332 % Yield = 53 ¹H: 3.08(3H, s), 7.1(3H, m), 7.2(2H, d,J=8.49Hz), 7.3-7.4(2H, m), 7.9(2H, d, J=8.5Hz). 125. S

Mol. Wt. = 348 % Yield = 60 ¹H, CD₃OD: 3.8(3H, s), 6.8(1H, s), 7.0(1H,d, J=8.0Hz), 7.09-7.16(2H, m), 7.3-7.4(1H, dd, J=6.3 & 8.0Hz), 7.6 (2H,d, J=8.6Hz), 8.0(2H, d, J=8.6Hz). 126. S

Mol. Wt. = 399 % Yield = 61 ¹H, dMSO-d₆: 3.5(3H, s), 6.9(1H, s), 7.2(1H,dd, J=2.4 & 8.5Hz), 7.5(2H, d, J=8.5Hz), 7.6(1H, d, J=8.5Hz), 7.7 (1H,d, J=2.4Hz), 7.9(2H, d, J=8.4Hz).

Preparation 7 3-(3,4-Dichlorophenyl)-4-[4-(N-chloroacetyl)methylsulfoximinylphenyl]-3H-oxazol-2-one (Compound No. 128)

To a solution of3-(3,4-dichlorophenyl)-4-[4-methylsulfoximinylphenyl]-3H-oxazol-2-one(Compound No. 119) (100 mg) and triethyl amine (0.18 mL) in dry THF (5mL) was added chloroacetyl chloride (59 mg) at 0° C. The reactionmixture was allowed to warm upto 25° C. and stirred for 2 h. Thereaction mixture was washed with water extracted with dichloromethane(3×10 mL). The organic extract was washed with water followed by brinesolution, dried over calcium chloride and evaporated under reducedpressure. The crude product was purified over silicagel using 50% ethylacetate in petroleum ether as eluent yielding 70 mg of product as ayellow solid.

In like manner following compounds in table 12 were prepared by aprocedure similar to that described above.

TABLE 12

Compound No. R₁ R₃ Mol. Wt Yield 127.

Mol. Wt. = 424 % Yield = 69 ¹H: 2.1(3H, s), 3.3(3H, s), 6.9(1H, d, J=2.4& 8.5Hz), 7.1(1H, s), 7.3(2H, d, J=8.5Hz), 7.4(1H, d, J=2.5Hz), 7.4(1H,d, J=8.5 Hz), 7.9(2H, d, J=8.5Hz). 128.

Mol. Wt. = 460 % Yield = 50 ¹H: 3.3(3H, s), 4.1(2H, s), 6.9(1H, dd,J=2.5 & 8.5Hz), 7.1(1H, s), 7.3(2H, d, J=8.6Hz), 7.4(1H, d, J=2.4Hz),7.4(1H, d, J=8.5 Hz), 7.9(2H, d, J=8.67Hz). 129.

Mol. Wt. = 461 % Yield = 66 ¹H: 3.1(3H, s), 3.4(3H, s), 6.9(1H, dd,J=2.5 & 8.6Hz), 7.1(1H, s), 7.3(2H, d, J=8.5Hz), 7.4(1H, d, J=2.5Hz),7.4(1H, d, J=8.5 Hz), 7.9(2H, d, J=8.5Hz). 130.

Mol. Wt. = 537 % Yield = 53 ¹H: 2.4(3H, s), 3.4(3H, s), 6.9(1H, dd,J=2.5 & 8.6Hz), 7.1(1H, s), 7.2-7.3(4H, m), 7.4(1H, d, J=2.4Hz), 7.4(1H,d, J=8.6Hz), 7.8(2H, d, J=8.3Hz), 7.9(2H, d, J=8.6Hz).

Preparation 83-(4-Methoxyphenyl)-4-(4-methylsulfanyl)-5-methyl-isoxazole (CompoundNo. 138)

Step 1: Preparation of3-(4-methoxyphenyl)-4-(4-methylsulfanyl)-5-methyl-4,5-dihydro-isoxazol-5-ol

To a stirred solution of1-(4-methoxyphenyl)-2-(4-methylsulfanylphenyl)ethanone oxime (4.5 g) indry THE (30 mL), was added a solution of n-butyl lithium (1.3 M, 30.7mL) in hexane at −70° C. over a period of 30 minutes. The reactionmixture was warmed to 20° C. over a period of 2 h. To this was addedethyl acetate (2.1 mL) and the reaction mixture was stirred the sametemperature for 30 minutes. The reaction mixture was quenched with coldwater (100 mL) and extracted with ethyl acetate (3×100 mL). The organicextract was washed with water (100 mL), brine (100 mL), dried oversodium sulphate and evaporated under reduced pressure. The crude productwas chromatographed over silicagel using 10% ethyl acetate in petroleumether as eluent, yielding 4.1 g of pure product as a pale yellow solid.

Step 2: Preparation of3-(4-methoxyphenyl)-4-(4-methylsulfanyl)-5-methyl-isoxazole

A solution of3-(4-methoxyphenyl)-4-(4-methylsulfanyl)-5-methyl-4,5-dihydro-isoxazol-5-ol(2.1 g) and PTSA (100 mg) in benzene (20 mL) was refluxed for 30minutes. The reaction mixture was cooled to 25° C., diluted with 50 mLof benzene and washed with water (50 mL) followed by brine solution (50mL). The organic extract was dried over sodium sulphate and evaporatedunder reduced pressure to yield 1.7 g of product as a thick liquid.

Preparation 9 5-Chloro-4(4-methyl sulfanylphenyl)-3-phenyl isoxazole(compound No. 136)

Step 1: Preparation of 5-hydroxy-4(4-methylsulfanylphenyl)-3-phenylisoxazole

To a stirred solution of 1-phenyl-2-(4-methylsulfanylphenyl) ethanoneoxime (2.0 g) in dry THF (20 mL), was added a solution of n-butyllithium (0.98 M. 25 mL) in hexane at −70° C. over a period of 30minutes. The reaction mixture was warmed to 20° C. over a period of 2 h.To this was added solid CO₂ (25 g) and the reaction mixture was stirredat the same temperature for 30 minutes. The reaction mixture wasquenched with cold 1N HCl (20 mL) and extracted with ethyl acetate (3×50mL). The organic extract was washed with water (100 mL); brine (100 mL),dried over sodium sulphate and evaporated under reduced pressure. Thecrude product was chromatographed over silicagel using 10% ethyl acetatein petroleum ether as eluent, yielding 1.2 g of pure product as a thickliquid.

Step 2: Preparation of 5-chloro-4(4-methylsulfanylphenyl)-3-phenylisoxazole

To a mixture of 5-hydroxy-4(4-methylsulfanylphenyl)-3-phenyl isoxazole(Compound prepared in step 1) (0.6 g) and triethyamine (0.43 mL) wasadded POCl₃ (10 mL) under stirring and the reaction mixture was heatedto 70° C. for 4 h. Solvents were evaporated and the crude product waschromatographed over silicagel using petroleum ether as eluent to yield310 mg of product as a pale yellow solid.

In like manner compounds in the following table were prepared followingthe procedure described in preparation 8.

TABLE 13

Compound No. R₃ R₄ Mol. Wt % Yield 131.

Mol. Wt. = 295 % Yield = 44 ¹H: 1.3(3H, t, J=7.6Hz), 2.7(3H, s), 2.8(2H,q, J=7.6Hz), 7.2-7.6(9H, complex). 132.

—CH₂OCH₃ Mol. Wt. = 311 % Yield = 60 ¹H: 2.5(3H, s), 3.4(3H, s), 4.5(2H,s), 7.1-7.2(4H, m), 7.3(3H, m), 7.4(2H, m). 133.

—CH₃ Mol. Wt. = 299 % Yield = 35 ¹H: 2.4(3H, s), 2.7(3H, s), 7.0(2H, t,J=8.7Hz), 7.3(4H, m), 7.6(2H, d, J=8.4Hz). 134.

—CH₃ Mol. Wt. = 315.5 % Yield = 85 ¹H: 2.4(3H, s), 2.7(3H, s),7.2-7.3(6H, m), 7.6(2H, d, J=8.2Hz). 135.

Mol. Wt. = 295 % Yield = 23 ¹H: 1.2(3H, t, J=7.5Hz), 2.6(2H, q,J=7.5Hz), 2.8(3H, s), 7.3(3H, m), 7.4(4H, m), 7.7(2H, d, J=8.4Hz). 136.

—Cl Mol. Wt. = 301.5 % Yield = 49 ¹H: 2.7(3H, s), 7.2-7.4(7H, complex),7.6(2H, d, J=8.3Hz) 137.

—CH₃ Mol. Wt. = 281 % Yield = 94 ¹H: 2.45(3H, s), 2.5(3H, s), 7.1(2H, d,J=8.44Hz), 7.2(2H, d, J=8.44Hz), 7.3(3H, m), 7.4(2H, m) 138.

—CH₃ Mol. Wt. = 311 % Yield = 85 ¹H: 2.4(3H, s), 2.5(3H, s), 3.8(3H, s),6.8(2H, dd, J=6.8 & 2.0Hz), 7.1(2H, dd, J=6.5 & 1.9Hz). 7.2(2H, dd,J=6.57 & 1.9Hz), 7.3(2H, dd, J=6.8 & 2.0Hz)

The sulfides of table 13 were converted to the corresponding sulfoxidesby a procedure similar to that described in preparation 2:

TABLE 14

Compound No. R₃ R₄ Mol. Wt Yield 139.

Mol. Wt. = 311 % Yield = 67 ¹H: 1.3(3H, t, J=7.6Hz), 2.7(3H, s), 2.8(2H,q, J=7.6Hz), 7.2-7.6(9H, complex). 140.

—CH₂OCH₃ Mol. Wt. = 327 % Yield = 72 141.

—CH₃ Mol. Wt. = 315 % Yield = 87 ¹H: 2.4(3H, s), 2.7(3H, s), 7.0(2H, t,J=8.7Hz), 7.3(4H, m), 7.6(2H, d, J=8.4Hz). 142.

—CH₃ Mol. Wt. = 331.5 % Yield = 79 ¹H: 2.4(3H, s), 2.7(3H, s),7.2-7.3(6H, m), 7.6(2H, d, J=8.2Hz). 143.

Mol. Wt. = 311 % Yield = 71 ¹H: 1.2(3H, t, J=7.5Hz), 2.6(2H, q,J=7.5Hz), 2.8(3H, s), 7.3(3H, m), 7.4(4H, m), 7.7(2H, d, J=3.4Hz). 144.

—Cl Mol. Wt. = 317.5 % Yield = 51 ¹H: 2.7(3H, s), 7.2-7.4(7H, complex),7.6(2H, d, J=8.3Hz) 145.

—CH₃ Mol. Wt. = 297 % Yield = 72 ¹H: 2.5(3H, s), 2.8 (3H, s),7.3-7.4(7H, m), 7.6(2H, d, J=8.5Hz) 146.

—CH₃ Mol. Wt. = 327 % Yield = 78 ¹H: 2.5(3H, s), 2.8(3H, s), 3.8(3H, s),6.8(2H, dd, J=6.82 & 2.02Hz), 7.3(4H, m), 7.6(2H, d, J=8.3Hz)

The sulfoxides of table 14 were converted to the correspondingsulfoximines by a procedure similar to that described in preparation 3:

TABLE 15

Compound No. R₃ R₄ Mol. Wt Yield 147.

Mol. Wt. = 326 % Yield = 71 ¹H, dMSO-d₆: 1.3(3H, t, J=7.6Hz), 2.8(2H, q,J=7.6Hz), 3.79(3H, s), 7.4(5H, m), 7.6(2H, d, J=8.5Hz), 8.1(2H, d,J=8.5Hz). 148.

—CH₂OCH₃ Mol. Wt. = 342 % Yield = 26 ¹H, dMSO-d₆: 3.3(3H, s), 3.4(3H,s), 4.5(2H, s), 7.4(5H, m), 7.5(2H, d, J=8.4 Hz), 8.0(2H, d, J=8.4Hz).149.

—CH₃ Mol. Wt. = 330 % Yield = 41 ¹H: 2.4(3H, s), 2.7(3H, s), 7.0(2H, t,J=8.7Hz), 7.3(4H, m), 7.6(2H, d, J=8.4Hz). 150.

—CH₃ Mol. Wt. = 346.5 % Yield = 86 ¹H, dMSO-d₆: 3.4(3H, s), 3.5(3H, s),7.3(2H, d, J=8.5Hz), 7.4(2H, d, J=8.5Hz), 7.5(2H, d, J=8.4Hz), 8.0(2H,d, J=8.7Hz). 151.

Mol. Wt. = 326 % Yield = 63 ¹H, dMSO-d₆: 1.1(3H, t, J=7.5Hz), 2.6(2H, q,J=7.5Hz), 3.6(3H, s), 7.4(5H, m), 7.7(2H, d, J=8.4Hz), 8.1(2H, d,J=8.4Hz). 152.

—Cl Mol. Wt. = 332.5 % Yield = 57 ¹H, dMSO-d₆: 3.3(3H, s), 7.3-7.4(5H,m), 7.5(2H, d, J=8.4Hz), 8.0(2H, d, J=8.4Hz) 153.

—CH₃ Mol. Wt. = 312 % Yield = 87 ¹H: 2.5(3H, s), 3.2(3H, s), 7.3-7.4(7H,m), 7.6(2H, dd, J=6.7 & 1.8Hz) 154.

—CH₃ Mol. Wt. = 342 % Yield = 30.2 ¹H: 2.5(3H, s), 3.1(3H, s), 3.8(3H,s), 6.8(2H, d, J=8.8Hz), 7.3(4H, m), 8.0(2H, d, J=8.3Hz)

Preparation 105-(4-Methylsulfoximinylphenyl)-1-phenyl-3-trifluoromethyl-1H-pyrazole(Compound No. 155)

Step 1: Preparation of5-(4-methylsulfanylphenyl)-1-phenyl-3-trifluoromethyl-1H-pyrazole

A solution of 4,4,4-trifluoro-(4-methylsulfanylphenyl)-butane-1,3-dione(3.0 g) and phenyl hydrazine hydrochloride (1.18 g) in ethanol (20 mL)was refluxed for 7 h. The solvent was evaporated and the residue waschromatographed over silicagel using 20% ethyl acetate in petroleumether as eluent yielding 2.25 g (% yield=83, Mol. Weight=334) of productas a gum.

¹H: 2.4(3H, s) 6.7(1H, s), 7.12(2H, dd, J=6.3 & 2.3 Hz), 7.15(2H, dd,J=6.3 & 2.2 Hz), 7.3(5H, m).

Step 2: Preparation of5-(4-methylsulfinylphenyl)-1-phenyl-3-trifluoromethyl-1H-pyrazole

Title compound (1.3 g, % yield=60, Mol. weight=350) was prepared from5-(4-methyl sulfanylphenyl)-1-phenyl-3-trifluoromethyl-1H-pyrazole (2.1g) (prepared in step 1 above) by a procedure similar to that describedin preparation 2.

¹H: 2.7 (3H, s), 6.8(1H, s), 7.3(2H, dd, J=6.2 & 2.0 Hz), 7.4(5H, m),7.6(2H, dd, J=8.2 & 1.6 Hz),

Step 3: Preparation of5-(4-methylsulfoximinylphenyl)-1-phenyl-3-trifluoromethyl-1H-pyrazole(Compound. No. 155)

Title compound (310 mg, % yield=45, Mol. weight=365) was prepared from5-(4-methyl sulfinylphenyl)-1-phenyl-3-trifluoromethyl-1H-pyrazole (600mg)(prepared in step 2 above) by a procedure similar to that describedin preparation 3.

¹H, CD₃OD: 3.8(3H, s), 7.17(1H, s), 7.3(2H, m), 7.4(3H, m), 7.7(2H, dd,J=8.7 & 1.8 Hz), 8.1(2H, dd, J=8.7 & 1.8 Hz).

Preparation 11 Hydrochloride salt of5-(3-fluoro-4-methoxyphenyl)-1-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole(Compound No. 167)

To5-(3-fluoro-4-methoxyphenyl)-1-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole(Compound. No. 74) (500 mg), methanolic HCl (10 mL, 15%) was added andstirred at 25-30° C. for 0.5 h. The solvent was evaporated under reducedpressure and the residual oil was stirred with diisopropyl ether toafford the product (440 mg) as a off white solid.

Preparation 12 Bisulphate salt of5-(3-methoxy-4-methylphenyl)-1-(4-methylsulfoximinyl-phenyl)-3-trifluoromethyl-1H-pyrazole(Compound No. 168)

To5-(3-methoxy-4-methylphenyl)-1-(4-methylsulfoxminylphenyl)-3-trifluoromethyl-1H-pyrazole(Compound No. 75) (120 mg), a chilled solution of acetone (10 mL)containing sulfuric acid (28 mg) was added and stirred at 0° C. for 30minutes. The solvent was evaporated under a flow of nitrogen and theresidue was stirred with diisopropyl ether to afford the product (75 mg)as an off white solid.

In like manner compounds in the table 16 were prepared following theprocedure described for the preparation of 11-12.

TABLE 16 Compound No. Free-base No. Salt prepared Melting Point (° C.)*156. 61 HCl 182 157. 62 HCl 200 158. 63 HCl 171 159. 64 HCl 178 160. 66HCl 163 161. 68 H₂SO₄ 135 162. 69 H₂SO₄ 195 163. 70 HCl 150 164. 71 HCl170 165. 72 HCl 178 166. 73 HCl 170 167. 74 HCl 168 168. 75 H₂SO₄ 192169. 77 HCl 68 170. 78 HCl 163 171. 79 H₂SO₄ 141 172. 80 H₂SO₄ 181 173.81 H₂SO₄ 165 174. 82 H₂SO₄ 174 175. 83 H₂SO₄ 199 176. 84 H₂SO₄ 214 177.85 H₂SO₄ 115 178. 92 HCl 168 179. 121 HCl 178 180. 123 HCl 184 181. 124HCl 170 182. 125 HCl 120 183. 126 HCl 176 184. 147 HCl 166 185. 148 HCl171 186. 149 HCl 169 187. 151 HCl 169 188. 152 HCl 158 189. 153 HCl 168190. 155 HCl 153 *The melting points were uncorrected and may vary inthe range of ±4° C.

1. A compound of formula (I), their tautomers, their pharmaceuticallyacceptable salts, and their pharmaceutically acceptable compositions,wherein G represents one of A, B, C, E, or F as described below:

R₁ represents hydrogen, substituted or unsubstituted groups selected thegroup consisting of from alkyl, aralkyl, acyl, alkylsulfonyl, andarylsulfonyl groups; R₂ represents alkyl, aralkyl, alkoxy or —NHR whereR represents hydrogen or a lower alkyl group which may be suitablysubstituted; X₁, X₂, X₃, and X₄ may be same or different and representhydrogen, cyano, nitro, halo, carboxyl, formyl, hydrazino, azido, amino,thio, hydroxy, or a substituted or unsubstituted group selected from thegroup consisting of alkyl which may be linear or branched, alkenyl,cycloalkyl, alkoxy, cycloalkoxy, cycloalkoxyalkyl, haloalkoxy,hydroxyalkyl, alkoxyalkyl, thioalkyl, carboxyalkyl, haloalkyl,aminoalkyl, cyanoalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl,alkoxycarbonylalkyl, acyl, acyloxy, acyloxyalkyl, aralkyl, aryloxy,aralkoxy, aryloxyalkyl, aralkoxyalkyl, aralkenyl, acylamino, alkylamino,dialkylamino, aralkylamino, alkoxyamino, hydroxylamino, alkoxycarbonyl,and aralkoxycarbonyl groups; R₃ represents a substituted orunsubstituted alkyl, or a substituted or unsubstituted, single or fusedgroup selected from the group consisting of aryl, aralkenyl, heteroaryl,and heterocyclic groups; R₄ and R₅ represent hydrogen atom, halogenatom, carboxy, or a substituted or unsubstituted group selected from thegroup consisting of linear or branched alkyl, alkoxycarbonyl,hydroxyalkyl, alkoxyalkyl, and phenyl groups; Y represents O or S; and Wrepresents O or S.
 2. The compound as claimed in claim 1, wherein thesubstituents on R₃ and R₄ represent a cyano, nitro, halo, carboxyl,amino, thio, hydroxy, or a substituted or unsubstituted group selectedfrom the group consisting of alkyl which may be linear or branched,perhaloalkyl, alkoxy, acyl, acyloxy, oxo, carboxyalkyl, haloalkyl,aminoalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, thioalkyl, alkylthio,alkylsulfinyl, alkylsulfonyl, alkylsulfoximinyl, acylamino,N-alkylamino, N,N-dialkylamino, alkoxycarbonyl, aminocarbonyl, and-ofcycloalkyl groups.
 3. The compound as claimed in claim 1,wherein thesubstituents on X₁, X₂, X₃, and X₄ represent a cyano, nitro, halo,carboxyl, hydrazino, azido, formyl, amino, thio, hydroxy or asubstituted or unsubstituted group selected from the group consisting ofalkyl which may be linear or branched, alkoxy, alkoxycarbonyl, acyl,acylamino, acyloxy, hydrazinoalkyl, alkylhydrazido, carboxyalkyl,haloalkyl, aminoalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, thioalkyl,alkylthio, alkylsulfinyl, alkylsulfonyl, aryl, aralkyl, aryloxy,aralkoxy, aryloxyalkyl, aralkoxyalkyl, alkoxycarbonyl, and amidinogroups.
 4. The compound as claimed in claim 1, wherein thepharmaceutically acceptable salts are salts of tartaric acid, mandelicacid, fumaric acid, malic acid, lactic acid, maleic acid, salicylicacid, citric acid, ascorbic acid, benzene sulfonic acid, p-toluenesulfonic acid, hydroxynaphthoic acid, methane sulfonic acid, aceticacid, benzoic acid, succinic acid, palmitic acid, hydrochloric acid,hydrobromic acid, sulfuric acid, or nitric acid.
 5. A pharmaceuticalcomposition comprising one or more compounds as claimed in claim 1 or apharmaceutically-acceptable salt thereof and apharmaceutically-acceptable carrier, diluent, excipient, or solvate. 6.The pharmaceutical composition as claimed in claim 1, in the form of atablet, capsule, powder, granule, syrup, solution, or suspension.
 7. Apharmaceutical composition which comprises a pharmaceutically-acceptablesalt as claimed in claim 4 and a pharmaceutically-acceptable carrier,diluent, excipient, or solvate.
 8. The pharmaceutical composition asclaimed in claim 7, in the form of a tablet, capsule, powder, granule,syrup, solution, or suspension.
 9. A method of treating pain, fever, orinflammation in a subject, said method comprising treating the subjecthaving or susceptible to such disorder with a therapeutically-effectiveamount of a compound as claimed in claim 1 or a pharmaceuticallyacceptable salt thereof.
 10. The method as claimed in claim 9, whereinthe compound is administered orally, nasally, parenterally, topically,transdermally, or rectally.
 11. A method of treating pain, fever, orinflammation in a subject, said method comprising treating the subjecthaving or susceptible to such disorder with a therapeutically-effectiveamount of a pharmaceutically-acceptable salt as claimed in claim
 4. 12.The method as claimed in claim 11, wherein thepharmaceutically-acceptable salt is administered orally, nasally,parenterally, topically, transdermally, or rectally.
 13. The compound asclaimed in claim 1 which is selected from the group consisting of:5-(4-Fluorophenyl)-1-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole;5-(4-Chlorophenyl)-1-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole;5-(4-Methylphenyl)-1-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole;5-(4-Methoxyphenyl)-1-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole;1-(4-methylsulfoximinylphenyl)-5-(4-n-propoxyphenyl)-3-trifluoromethyl-1H-pyrazole;5-(4-Ethoxyphenyl)-1-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole;5-(4-Hydroxyphenyl)-1-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole;5-(3-Chloro-4-fluorophenyl)-1-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole;5-(3,4-Difluorophenyl)-1-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole;5-(4-Fluoro-3-methylphenyl)-1-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole;5-(4-Methoxy-3-methylphenyl)-1-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole;5-(3-Chloro-4-methoxyphenyl)-1-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole;5-(3-Bromo-4-methoxyphenyl)-1-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole;5-(3-Fluoro-4-methoxyphenyl)-1-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole;5-(3-Methoxy-4-methylphenyl)-1-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole;1-(2-Fluoro-4-methylsulfoximinylphenyl)-5-(4-Methoxyphenyl)-3-trifluoromethyl-1H-pyrazole;1-(3-Fluoro-4-methylsulfoximinylphenyl)-5-(4-Methoxyphenyl)-3-trifluoromethyl-1H-pyrazole;1-(4-Methylsulfoximinylphenyl)-5-phenyl-3-trifluoromethyl-1H-pyrazole;1-(4-Methylsulfoximinylphenyl)-5-(1-naphthyl)-3-trifluoromethyl-1H-pyrazole;5-(4-Methoxyphenyl)-3-methyl-1-(4-methylsulfoximinylphenyl)-1H-pyrazole;1-(4-Methylsulfoximinylphenyl)-5-(4-nitrophenyl)-3-trifluoromethyl-1H-pyrazole;5-(3-Methoxyphenyl)-1-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole;5-(3,5-Difluoro-4-Methoxyphenyl)-1-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole;5-(3-Hydroxy-4-methoxyphenyl)-1-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole;5-(4-Methoxyphenyl)-1-(4-methylsulfoximinylphenyl)-1H-pyrazole-3-carboxylicacid;3-(Hydroxymethyl)-5-(4-Methoxyphenyl)-1-(4-methylsulfoximinylphenyl)-1H-pyrazole;5-(4-Methoxyphenyl)-1-(4-methylsulfoximinylphenyl)-1H-pyrazol-3-ylmethylhydrogensulphate;5-{4-(2-Hydroxy-ethoxy)phenyl}-1-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole;1-(4-Methylsulfoximinylphenyl)-5-(4-pyridyl)-3-trifluoromethyl-1H-pyrazole;1-(4-Methylsulfoximinylphenyl)-5-(3-pyridyl)-3-trifluoromethyl-1H-pyrazole;1-(4-Methylsulfoximinylphenyl)-5-(2-pyridyl)-3-trifluoromethyl-1H-pyrazole;5-(4-Isopropoxyphenyl)-1-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole;1-(4-Methylsulfoximinylphenyl)-5-(2-thiophenyl)-3-trifluoromethyl-1H-pyrazole;5-(4-Methylsulfoxyminylphenyl)-1-phenyl-3-trifluoromethyl-1H-pyrazole;1-(4-Methoxyphenyl)-5-(4-methylsulfoximinylphenyl)-3-trifluoromethyl-1H-pyrazole;5-Ethyl-4-(4-methylsulfoximinylphenyl)-3-phenyl-isoxazole;5-Methoxymethyl-4-(4-methylsulfoximinylphenyl)-3-phenyl-isoxazole;3-(4-Fluorophenyl)-5-methyl-4-(4-methylsulfoximinylphenyl)-isoxazole;3-(4-Chlorophenyl)-5-methyl-4-(4-methylsulfoximinylphenyl)-isoxazole;3-Ethyl-4-(4-methylsulfoximinylphenyl)-5-phenyl-isoxazole;5-Chloro-4-(4-methylsulfoximinylphenyl)-3-phenyl-isoxazole;5-Methyl-4-(4-methylsulfoximinylphenyl)-3-phenyl-isoxazole;3-(4-Methoxyphenyl)-5-methyl-4-(4-methylsulfoximinylphenyl)-isoxazole;5-Chloro-3-(4-methylsulfoximinylphenyl)-6′-methyl-[2,3′]bipyridinyl;5-Chloro-3-(4-methylsulfoximinylphenyl)-[2,3′]bipyridinyl;3-(3-Fluorophenyl)-4-(4-methylsulfoximinylphenyl)-3H-thiazol-2-one;3-(3,4-Dichlorophenyl)-4-(4-methylsulfoximinylphenyl)-3H-oxazol-2-one;3-(3,4-Dichlorophenyl)-4-(4-methylsulfoximinylphenyl)-3H-thiazol-2-one;3-(2-Fluorophenyl)-4-(4-methylsulfoximinylphenyl)-3H-oxazol-2-one;3-(4-Bromophenyl)-4-(4-methylsulfoximinylphenyl)-3H-oxazol-2-one;4-(4-Methylsulfoximinylphenyl)-3-phenyl-3H-oxazol-2-one;3-(3,4-Dichlorophenyl)-4-[4-(N-chloroacetyl)methylsulfoximinyl-phenyl]-3H-oxazol-2-one;3-(3,4-Dichlorophenyl)-4-[4-(N-acetyl)methylsulfoximinyl-phenyl]-3H-oxazol-2-one;3-(3,4-Dichlorophenyl)-4-[4-(N-methylsulfonyl)methylsulfoximinyl-phenyl]-3H-oxazol-2-one;3-(3,4-Dichlorophenyl)-4-[4-{N-(4-methylphenyl)sulfonyl}-methylsulfoximinyl-phenyl]-3H-oxazol-2-one;and pharmaceutically-acceptable salts thereof.
 14. The compound asclaimed in claim 13, wherein the pharmaceutically acceptable salts aresalts of tartaric acid, mandelic acid, fumaric acid, malic acid, lacticacid, maleic acid, salicylic acid, citric acid, ascorbic acid, benzenesulfonic acid, p-toluene sulfonic acid, hydroxynaphthoic acid, methanesulfonic acid, acetic acid, benzoic acid, succinic acid, palmitic acid,hydrochloric acid, hydrobromic acid, sulfuric acid, or nitric acid. 15.A pharmaceutical composition, which comprises a compound orpharmaceutically-acceptable salt thereof as claimed in claim 13, and apharmaceutically acceptable carrier, diluent, excipient, or solvate. 16.The pharmaceutical composition as claimed in claim 15, in the form of atablet, capsule, powder, granules, syrup, solution, or suspension.
 17. Amethod of treating pain, fever, or inflammation in a subject, saidmethod comprising treating the subject having or susceptible to suchdisorder with a therapeutically-effective amount of a compound orpharmaceutically acceptable salt thereof as claimed in claim
 13. 18. Aprocess for preparing a compound of formula (I),

wherein G represents one of A, B, C, E, or F as desenbed below:

R₁ represents hydrogen, substituted or unsubstituted groups selectedfrom the group consisting of alkyl, aralkyl, acyl, alkylsulfonyl, andarylsulfonyl groups; R₂ represents alkyl, aralkyl, or —NHR or —OR whereR represents hydrogen or a lower alkyl group which may be suitablysubstituted; X₁, X₂, X₃, and X₄ may be same or different and representhydrogen, cyano, nitro, halo, carboxyl, formyl, hydrazino, azido, amino,thio, hydroxy, or a substituted or unsubstituted group selected from thegroup consisting of alkyl which may be linear or branched, alkenyl,oximealkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkoxyalkyl, thioalkyl,carboxyalkyl, haloalkyl, aminoalkyl, cyanoalkyl, alkylthio,alkylsulfinyl, alkylsulfonyl, alkoxycarbonylalkyl, acyl, acyloxy,acyloxyalkyl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, aralkoxyalkyl,aralkenyl, acylamino, alkylamino, dialkylamino, aralkylamino,alkoxyamino, hydroxylamino, alkoxycarbonyl, and aralkoxycarbonyl groups;when G represents heterocycle “D”, then at least one of X₁, X₂, X₃, andX₄ is not hydrogen; R₃ represents a substituted or unsubstituted alkyl,or a substituted or unsubstituted, single or fused group selected fromthe group consisting of aryl, aralkenyl, heteroaryl, and heterocyclicgroups; R₄ and R₅ represent hydrogen atom, halogen atom, carboxy, or asubstituted or unsubstituted group selected from the group consisting oflinear or branched alkyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, andphenyl groups; Y represents O or S; and W represents O or S; saidprocess comprising: (a) oxidizing a compound of formula (P) to produce acompound of formula (Q) and (b) iminating the compound of formula (Q) toproduce a compound of formula (I)


19. The process as claimed in claim 18 further comprising converting thecompound of formula (I) to its pharmaceutically-acceptable salt.